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Mutations could be therapeutic target for FL
Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.
They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.
And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.
Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.
“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.
“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”
Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.
In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.
Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.
“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”
The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.
“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.” 
Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.
They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.
And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.
Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.
“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.
“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”
Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.
In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.
Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.
“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”
The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.
“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”
Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.
They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.
And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.
Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.
“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.
“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”
Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.
In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.
Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.
“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”
The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.
“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”
Cancer drug discovery database goes 3D
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
EZH2 inhibitor can produce durable responses
ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).
The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.
In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.
The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.
At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.
The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.
The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.
Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.
Safety
At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.
Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).
There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.
Efficacy
Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).
Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.
Four responders remain on study—2 with DLBCL and 2 with FL.
One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.
Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.
*Data in the abstract differ from the presentation.
ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).
The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.
In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.
The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.
At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.
The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.
The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.
Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.
Safety
At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.
Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).
There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.
Efficacy
Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).
Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.
Four responders remain on study—2 with DLBCL and 2 with FL.
One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.
Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.
*Data in the abstract differ from the presentation.
ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).
The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.
In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.
The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.
At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.
The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.
The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.
Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.
Safety
At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.
Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).
There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.
Efficacy
Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).
Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.
Four responders remain on study—2 with DLBCL and 2 with FL.
One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.
Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.
*Data in the abstract differ from the presentation.
Tool may provide new insight into pediatric cancers
and Xin Zhou, PhD
Photo by Peter Barta/St. Jude
Children’s Research Hospital
Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.
The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.
ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.
That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.
ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.
ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.
Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.
“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”
Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.
ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.
ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.
More information about ProteinPaint is available on the St. Jude PeCan Data Portal.
and Xin Zhou, PhD
Photo by Peter Barta/St. Jude
Children’s Research Hospital
Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.
The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.
ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.
That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.
ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.
ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.
Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.
“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”
Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.
ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.
ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.
More information about ProteinPaint is available on the St. Jude PeCan Data Portal.
and Xin Zhou, PhD
Photo by Peter Barta/St. Jude
Children’s Research Hospital
Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.
The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.
ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.
That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.
ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.
ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.
Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.
“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”
Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.
ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.
ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.
More information about ProteinPaint is available on the St. Jude PeCan Data Portal.
Factors predict low accrual in cancer clinical trials
for a clinical trial
Photo by Esther Dyson
Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.
Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.
However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.
Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.
They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.
After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.
The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
Those 12 risk factors are:
- The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
- Phase 3 vs phase 2 trial (OR=1.86)
- Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
- Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
- Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
- Tissue sample required to assess eligibility (OR=1.26)
- Investigational new drug (OR=0.34)
- Metastatic setting (OR=1.46)
- Sample size per 100 (OR=0.95)
- More than one condition evaluated (OR=1.98)
- Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
- Interaction term (phase 3 x investigational new drug, OR=2.47).
The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.
for a clinical trial
Photo by Esther Dyson
Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.
Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.
However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.
Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.
They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.
After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.
The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
Those 12 risk factors are:
- The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
- Phase 3 vs phase 2 trial (OR=1.86)
- Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
- Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
- Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
- Tissue sample required to assess eligibility (OR=1.26)
- Investigational new drug (OR=0.34)
- Metastatic setting (OR=1.46)
- Sample size per 100 (OR=0.95)
- More than one condition evaluated (OR=1.98)
- Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
- Interaction term (phase 3 x investigational new drug, OR=2.47).
The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.
for a clinical trial
Photo by Esther Dyson
Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.
Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.
However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.
Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.
They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.
After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.
The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
Those 12 risk factors are:
- The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
- Phase 3 vs phase 2 trial (OR=1.86)
- Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
- Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
- Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
- Tissue sample required to assess eligibility (OR=1.26)
- Investigational new drug (OR=0.34)
- Metastatic setting (OR=1.46)
- Sample size per 100 (OR=0.95)
- More than one condition evaluated (OR=1.98)
- Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
- Interaction term (phase 3 x investigational new drug, OR=2.47).
The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.
Heavily pretreated myeloma responds to pembrolizumab combo
ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.
ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.
ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.
AT ASH 2015
Key clinical point: Initial results show promising activity for pembrolizumab in combination with lenalidomide and low-dose dexamethasone in heavily pretreated relapsed or refractory multiple myeloma.
Major finding: The overall response rate was 76% (13/17 patients).
Data source: Phase I study in 50 patients with relapsed or refractory multiple myeloma.
Disclosures: The study was supported by Merck. Dr. San Miguel reported consulting for Merck and relationships with Millennium, Janssen, Celgene, Novartis, Onyx, Bristol-Myers Squibb, and Sanofi.
Education may increase clinical trial participation
Photo courtesy of NCI
and Matthews Media Group
A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.
After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.
Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.
“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.
“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”
Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.
The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.
PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.
For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.
Results
Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.
Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).
Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).
Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.
Financial concerns
During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.
These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.
“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”
“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”
The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.
Photo courtesy of NCI
and Matthews Media Group
A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.
After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.
Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.
“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.
“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”
Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.
The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.
PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.
For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.
Results
Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.
Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).
Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).
Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.
Financial concerns
During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.
These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.
“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”
“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”
The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.
Photo courtesy of NCI
and Matthews Media Group
A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.
After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.
Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.
“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.
“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”
Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.
The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.
PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.
For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.
Results
Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.
Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).
Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).
Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.
Financial concerns
During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.
These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.
“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”
“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”
The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.
Protein discovery could have therapeutic implications
Photo courtesy of The
Scripps Research Institute
New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.
This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.
Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.
Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.
Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.
Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.
The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.
These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.
This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.
However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.
The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.
The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.
“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.
He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins.
Photo courtesy of The
Scripps Research Institute
New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.
This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.
Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.
Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.
Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.
Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.
The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.
These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.
This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.
However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.
The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.
The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.
“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.
He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins.
Photo courtesy of The
Scripps Research Institute
New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.
This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.
Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.
Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.
Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.
Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.
The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.
These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.
This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.
However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.
The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.
The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.
“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.
He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins.
Survey reveals need to evaluate EOL discussions
Photo courtesy of the
National Cancer Institute
and Mathews Media Group
End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.
The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,
which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.
So it may not be clear that a patient has entered the EOL phase.
Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.
The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.
Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.
Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.
Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).
When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.
The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.
Photo courtesy of the
National Cancer Institute
and Mathews Media Group
End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.
The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,
which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.
So it may not be clear that a patient has entered the EOL phase.
Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.
The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.
Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.
Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.
Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).
When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.
The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.
Photo courtesy of the
National Cancer Institute
and Mathews Media Group
End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.
The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,
which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.
So it may not be clear that a patient has entered the EOL phase.
Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.
The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.
Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.
Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.
Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).
When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.
The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.
Antibody shows promise for treating CLL
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.