Leukemia, Myelodysplasia, Transplantation

Study authors Christian

Schürch, MD, PhD, (left)

and Adrian Ochsenbein, MD

Photo by Susi Bürki

Combining a tyrosine kinase inhibitor (TKI) with a monoclonal antibody (mAb) may circumvent TKI resistance in chronic myeloid leukemia (CML), according to preclinical research published in Science Translational Medicine.

To understand how TKI resistance develops, researchers analyzed the effect of these drugs on BCR-ABL1⁺ leukemia cell lines, cells from patients with newly diagnosed CML, and mouse models of CML.

The team found that TKIs induce CD70 expression in leukemic stem cells (LSCs) by downregulating microRNA-29. This results in reduced CD70 promoter DNA methylation and upregulation of the transcription factor specificity protein 1 (SP1).

The increase in CD70 triggers CD27 signaling and compensatory Wnt pathway activation. The researchers said this suggests LSCs evade TKIs by activating Wnt signaling through this route.

So the team hypothesized that combination treatment with a TKI and a mAb blocking the CD70/CD27 interaction would eradicate LSCs.

First, they tested an αCD27 mAb alone or in combination with a TKI in leukemia cell lines. Compared to either agent alone, αCD27/imatinib cotreatment significantly (P<0.001) reduced cell growth by inhibiting proliferation and enhancing apoptosis in SD-1 cells.

The researchers observed similar results when they tested the αCD27 mAb and nilotinib in SD-1 cells, as well as when they tested the αCD27 mAb with imatinib or ponatinib in KBM5 and KBM5r cells.

The team noted that αCD27/imatinib cotreatment inhibited Wnt pathway activation significantly stronger than either compound alone (P<0.001) but had little to no effect on Notch, Hedgehog, and MAP kinase pathways.

The researchers also conducted in vitro tests with an αCD70 mAb (clone 41D12-D) that was specifically designed to block the CD70/CD27 interaction without inducing effector functions such as antibody-dependent cell- or complement-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis.

They found that αCD70/imatinib cotreatment “potently reduced” CD34⁺ CML stem/progenitor cells in liquid cultures by inhibiting proliferation and increasing apoptosis. The combination also significantly impaired colony formation in semisolid cultures when compared to either agent alone (P<0.05).

In addition, αCD70/imatinib cotreatment eliminated human CD34⁺ CML stem/progenitor cells in murine xenografts. The LSCs were completely eradicated in 9 of 12 mice treated.

In a murine CML model, combination treatment with imatinib and an αCD70 mAb (clone FR70) significantly improved survival (P<0.001) compared to either agent alone. And 60% of mice (9 of 15) that received the combination were alive 90 days after transplantation.

The researchers said this suggests the LSCs were completely eradicated or at least effectively controlled long-term.

Study authors Christian

Schürch, MD, PhD, (left)

and Adrian Ochsenbein, MD

Photo by Susi Bürki

Combining a tyrosine kinase inhibitor (TKI) with a monoclonal antibody (mAb) may circumvent TKI resistance in chronic myeloid leukemia (CML), according to preclinical research published in Science Translational Medicine.

To understand how TKI resistance develops, researchers analyzed the effect of these drugs on BCR-ABL1⁺ leukemia cell lines, cells from patients with newly diagnosed CML, and mouse models of CML.

The team found that TKIs induce CD70 expression in leukemic stem cells (LSCs) by downregulating microRNA-29. This results in reduced CD70 promoter DNA methylation and upregulation of the transcription factor specificity protein 1 (SP1).

The increase in CD70 triggers CD27 signaling and compensatory Wnt pathway activation. The researchers said this suggests LSCs evade TKIs by activating Wnt signaling through this route.

So the team hypothesized that combination treatment with a TKI and a mAb blocking the CD70/CD27 interaction would eradicate LSCs.

First, they tested an αCD27 mAb alone or in combination with a TKI in leukemia cell lines. Compared to either agent alone, αCD27/imatinib cotreatment significantly (P<0.001) reduced cell growth by inhibiting proliferation and enhancing apoptosis in SD-1 cells.

The researchers observed similar results when they tested the αCD27 mAb and nilotinib in SD-1 cells, as well as when they tested the αCD27 mAb with imatinib or ponatinib in KBM5 and KBM5r cells.

The team noted that αCD27/imatinib cotreatment inhibited Wnt pathway activation significantly stronger than either compound alone (P<0.001) but had little to no effect on Notch, Hedgehog, and MAP kinase pathways.

The researchers also conducted in vitro tests with an αCD70 mAb (clone 41D12-D) that was specifically designed to block the CD70/CD27 interaction without inducing effector functions such as antibody-dependent cell- or complement-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis.

They found that αCD70/imatinib cotreatment “potently reduced” CD34⁺ CML stem/progenitor cells in liquid cultures by inhibiting proliferation and increasing apoptosis. The combination also significantly impaired colony formation in semisolid cultures when compared to either agent alone (P<0.05).

In addition, αCD70/imatinib cotreatment eliminated human CD34⁺ CML stem/progenitor cells in murine xenografts. The LSCs were completely eradicated in 9 of 12 mice treated.

In a murine CML model, combination treatment with imatinib and an αCD70 mAb (clone FR70) significantly improved survival (P<0.001) compared to either agent alone. And 60% of mice (9 of 15) that received the combination were alive 90 days after transplantation.

The researchers said this suggests the LSCs were completely eradicated or at least effectively controlled long-term.

Study authors Christian

Schürch, MD, PhD, (left)

and Adrian Ochsenbein, MD

Photo by Susi Bürki

Combining a tyrosine kinase inhibitor (TKI) with a monoclonal antibody (mAb) may circumvent TKI resistance in chronic myeloid leukemia (CML), according to preclinical research published in Science Translational Medicine.

To understand how TKI resistance develops, researchers analyzed the effect of these drugs on BCR-ABL1⁺ leukemia cell lines, cells from patients with newly diagnosed CML, and mouse models of CML.

The team found that TKIs induce CD70 expression in leukemic stem cells (LSCs) by downregulating microRNA-29. This results in reduced CD70 promoter DNA methylation and upregulation of the transcription factor specificity protein 1 (SP1).

The increase in CD70 triggers CD27 signaling and compensatory Wnt pathway activation. The researchers said this suggests LSCs evade TKIs by activating Wnt signaling through this route.

So the team hypothesized that combination treatment with a TKI and a mAb blocking the CD70/CD27 interaction would eradicate LSCs.

First, they tested an αCD27 mAb alone or in combination with a TKI in leukemia cell lines. Compared to either agent alone, αCD27/imatinib cotreatment significantly (P<0.001) reduced cell growth by inhibiting proliferation and enhancing apoptosis in SD-1 cells.

The researchers observed similar results when they tested the αCD27 mAb and nilotinib in SD-1 cells, as well as when they tested the αCD27 mAb with imatinib or ponatinib in KBM5 and KBM5r cells.

The team noted that αCD27/imatinib cotreatment inhibited Wnt pathway activation significantly stronger than either compound alone (P<0.001) but had little to no effect on Notch, Hedgehog, and MAP kinase pathways.

The researchers also conducted in vitro tests with an αCD70 mAb (clone 41D12-D) that was specifically designed to block the CD70/CD27 interaction without inducing effector functions such as antibody-dependent cell- or complement-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis.

They found that αCD70/imatinib cotreatment “potently reduced” CD34⁺ CML stem/progenitor cells in liquid cultures by inhibiting proliferation and increasing apoptosis. The combination also significantly impaired colony formation in semisolid cultures when compared to either agent alone (P<0.05).

In addition, αCD70/imatinib cotreatment eliminated human CD34⁺ CML stem/progenitor cells in murine xenografts. The LSCs were completely eradicated in 9 of 12 mice treated.

In a murine CML model, combination treatment with imatinib and an αCD70 mAb (clone FR70) significantly improved survival (P<0.001) compared to either agent alone. And 60% of mice (9 of 15) that received the combination were alive 90 days after transplantation.

The researchers said this suggests the LSCs were completely eradicated or at least effectively controlled long-term.

Preparing drug capsules

for a clinical trial

Photo by Esther Dyson

Pharmaceutical companies “underinvest” in long-term research to develop new anticancer drugs, according to a study published in American Economic Review.

Investigators used historical data to show that companies are more likely to develop drugs for late-stage cancers than early stage cancers or cancer prevention, and this is likely because late-stage cancer drugs can be brought to market faster.

The team found that late-stage drugs extend patient survival for shorter periods so that clinical trials for these drugs get wrapped up more quickly. This, in turn, gives drug manufacturers more time to control patented drugs in the marketplace.

“There is a pattern where we get more investment in drugs that take a short time to complete and less investment in drugs that take a longer time to complete,” said study author Heidi Williams, PhD, of the Massachusetts Institute of Technology in Cambridge.

To conduct this study, Dr Williams and her colleagues analyzed 4 decades of clinical trial data from a variety of sources, including the National Cancer Institute and the US Food and Drug Administration. The study encompassed more than 200 subcategories of cancers detected at different stages of development.

In analyzing the data, the investigators divided research and development (R&D) into 2 stages: invention (developing the basic idea for a product to the point where it is patentable) and commercialization (bringing an invented product to market).

They defined the “commercialization lag” of an R&D project as the amount of time between invention and commercialization.

The data showed that patient groups with longer commercialization lags (as proxied by longer survival times) tended to have lower levels of R&D investment than groups with shorter commercialization lags (and survival times).

The investigators also found that when surrogate endpoints (endpoints other than survival) were allowed, there were more trials and money poured into research. This supports the idea that companies are more likely to invest in drugs that will have shorter trials and take less time to develop.

Dr Williams and her colleagues used the surrogate endpoint variation to estimate improvements in cancer survival rates that would have been observed if commercialization lags were reduced. The team estimated that, among US cancer patients diagnosed in 2003, longer commercialization lags resulted in around 890,000 lost life-years.

The investigators noted that commercialization lags reduce both public and private R&D investments, but they found the commercialization lag-R&D correlation is significantly more negative for privately financed trials than publicly financed trials.

The team said that, due to either excessive discounting or the fixed patent term, private incentives decline more rapidly than public incentives, which is what gives rise to the distortion.

Based on their findings, Dr Williams and her colleagues devised 3 new policy approaches that could potentially spark the development of more drugs for early stage cancers or cancer prevention.

The first is expanded use of surrogate endpoints or more research to determine if wider use of surrogate endpoints is valid.

A second possible policy change is more public funding of R&D for anticancer drugs, since such funding is free of short-term, private-sector shareholder pressure to produce returns.

A third potential new policy would be changing the terms of drug patents, which typically run from the time of patent filing to when the drug hits the market.

Preparing drug capsules

for a clinical trial

Photo by Esther Dyson

Pharmaceutical companies “underinvest” in long-term research to develop new anticancer drugs, according to a study published in American Economic Review.

Investigators used historical data to show that companies are more likely to develop drugs for late-stage cancers than early stage cancers or cancer prevention, and this is likely because late-stage cancer drugs can be brought to market faster.

The team found that late-stage drugs extend patient survival for shorter periods so that clinical trials for these drugs get wrapped up more quickly. This, in turn, gives drug manufacturers more time to control patented drugs in the marketplace.

“There is a pattern where we get more investment in drugs that take a short time to complete and less investment in drugs that take a longer time to complete,” said study author Heidi Williams, PhD, of the Massachusetts Institute of Technology in Cambridge.

To conduct this study, Dr Williams and her colleagues analyzed 4 decades of clinical trial data from a variety of sources, including the National Cancer Institute and the US Food and Drug Administration. The study encompassed more than 200 subcategories of cancers detected at different stages of development.

In analyzing the data, the investigators divided research and development (R&D) into 2 stages: invention (developing the basic idea for a product to the point where it is patentable) and commercialization (bringing an invented product to market).

They defined the “commercialization lag” of an R&D project as the amount of time between invention and commercialization.

The data showed that patient groups with longer commercialization lags (as proxied by longer survival times) tended to have lower levels of R&D investment than groups with shorter commercialization lags (and survival times).

The investigators also found that when surrogate endpoints (endpoints other than survival) were allowed, there were more trials and money poured into research. This supports the idea that companies are more likely to invest in drugs that will have shorter trials and take less time to develop.

Dr Williams and her colleagues used the surrogate endpoint variation to estimate improvements in cancer survival rates that would have been observed if commercialization lags were reduced. The team estimated that, among US cancer patients diagnosed in 2003, longer commercialization lags resulted in around 890,000 lost life-years.

The investigators noted that commercialization lags reduce both public and private R&D investments, but they found the commercialization lag-R&D correlation is significantly more negative for privately financed trials than publicly financed trials.

The team said that, due to either excessive discounting or the fixed patent term, private incentives decline more rapidly than public incentives, which is what gives rise to the distortion.

Based on their findings, Dr Williams and her colleagues devised 3 new policy approaches that could potentially spark the development of more drugs for early stage cancers or cancer prevention.

The first is expanded use of surrogate endpoints or more research to determine if wider use of surrogate endpoints is valid.

A second possible policy change is more public funding of R&D for anticancer drugs, since such funding is free of short-term, private-sector shareholder pressure to produce returns.

A third potential new policy would be changing the terms of drug patents, which typically run from the time of patent filing to when the drug hits the market.

Preparing drug capsules

for a clinical trial

Photo by Esther Dyson

Pharmaceutical companies “underinvest” in long-term research to develop new anticancer drugs, according to a study published in American Economic Review.

Investigators used historical data to show that companies are more likely to develop drugs for late-stage cancers than early stage cancers or cancer prevention, and this is likely because late-stage cancer drugs can be brought to market faster.

The team found that late-stage drugs extend patient survival for shorter periods so that clinical trials for these drugs get wrapped up more quickly. This, in turn, gives drug manufacturers more time to control patented drugs in the marketplace.

“There is a pattern where we get more investment in drugs that take a short time to complete and less investment in drugs that take a longer time to complete,” said study author Heidi Williams, PhD, of the Massachusetts Institute of Technology in Cambridge.

To conduct this study, Dr Williams and her colleagues analyzed 4 decades of clinical trial data from a variety of sources, including the National Cancer Institute and the US Food and Drug Administration. The study encompassed more than 200 subcategories of cancers detected at different stages of development.

In analyzing the data, the investigators divided research and development (R&D) into 2 stages: invention (developing the basic idea for a product to the point where it is patentable) and commercialization (bringing an invented product to market).

They defined the “commercialization lag” of an R&D project as the amount of time between invention and commercialization.

The data showed that patient groups with longer commercialization lags (as proxied by longer survival times) tended to have lower levels of R&D investment than groups with shorter commercialization lags (and survival times).

The investigators also found that when surrogate endpoints (endpoints other than survival) were allowed, there were more trials and money poured into research. This supports the idea that companies are more likely to invest in drugs that will have shorter trials and take less time to develop.

Dr Williams and her colleagues used the surrogate endpoint variation to estimate improvements in cancer survival rates that would have been observed if commercialization lags were reduced. The team estimated that, among US cancer patients diagnosed in 2003, longer commercialization lags resulted in around 890,000 lost life-years.

The investigators noted that commercialization lags reduce both public and private R&D investments, but they found the commercialization lag-R&D correlation is significantly more negative for privately financed trials than publicly financed trials.

The team said that, due to either excessive discounting or the fixed patent term, private incentives decline more rapidly than public incentives, which is what gives rise to the distortion.

Based on their findings, Dr Williams and her colleagues devised 3 new policy approaches that could potentially spark the development of more drugs for early stage cancers or cancer prevention.

The first is expanded use of surrogate endpoints or more research to determine if wider use of surrogate endpoints is valid.

A second possible policy change is more public funding of R&D for anticancer drugs, since such funding is free of short-term, private-sector shareholder pressure to produce returns.

A third potential new policy would be changing the terms of drug patents, which typically run from the time of patent filing to when the drug hits the market.

Aik Choon Tan, PhD

Photo courtesy of the

University of Colorado

Researchers say they have developed a tool that allows us to determine which tyrosine kinase inhibitor (TKI) will be most effective against a certain type of cancer.

The tool, known as the Kinase Addiction Ranker (KAR), predicts the genetic abnormalities that are driving the cancer in any population of cells and chooses the best TKI or combination of TKIs to target these abnormalities.

The researchers described the tool in Bioinformatics.

“A lot of [TKIs] inhibit a lot more than what they’re supposed to inhibit,” said study author Aik Choon Tan, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.

“Maybe drug A was designed to inhibit kinase B, but it also inhibits kinase C and D as well. Our approach centers on exploiting the promiscuity of these drugs, the ‘drug spillover.’”

For each TKI, there is a signature describing the kinases each drug fully or partially inhibits. Dr Tan and his colleagues combined these kinase inhibition signatures with the results of high-throughput screening. They used the Genomics of Drug Sensitivity in Cancer database to determine which TKIs have already proven active against which cancer cell lines.

The result is KAR, which does 2 things. For any cancer cell line, the program ranks the kinases that are most important to the growth of the disease. Then, the program recommends the combination of existing TKIs that is likely to do the most good against the implicated kinases.

Dr Tan and his colleagues tested KAR using samples from 151 leukemia patients and found that, among the kinases analyzed, FLT3 had the highest variance in sensitivity to TKIs.

But EPHA5, EPHA3, and BTK were the kinases most commonly associated with drug sensitivity. They had significant associations in 72%, 58%, and 54% of the patient samples, respectively.

The researchers said the frequency of BTK dependence they observed is interesting given the fact that the BTK inhibitor ibrutinib produced favorable results in a phase 1b/2 trial of patients with chronic lymphocytic leukemia (CLL). The progression-free survival rate at 26 months was 75% in that trial.

Dr Tan and his colleagues said this was consistent with their findings, which showed that 70% of CLL patient data had a significant association between BTK inhibition and drug sensitivity.

The researchers also found that KAR could predict TKI sensitivity in 21 lung cancer cell lines. In addition, the tool was able to recommend a combination of TKIs that hindered proliferation in the lung cancer cell line H1581. KAR suggested ponatinib and the experimental anticancer agent AZD8055, and experiments showed that these drugs synergistically reduced proliferation in H1581.

KAR is available for download on the Tan lab’s website.

Aik Choon Tan, PhD

Photo courtesy of the

University of Colorado

Researchers say they have developed a tool that allows us to determine which tyrosine kinase inhibitor (TKI) will be most effective against a certain type of cancer.

The tool, known as the Kinase Addiction Ranker (KAR), predicts the genetic abnormalities that are driving the cancer in any population of cells and chooses the best TKI or combination of TKIs to target these abnormalities.

The researchers described the tool in Bioinformatics.

“A lot of [TKIs] inhibit a lot more than what they’re supposed to inhibit,” said study author Aik Choon Tan, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.

“Maybe drug A was designed to inhibit kinase B, but it also inhibits kinase C and D as well. Our approach centers on exploiting the promiscuity of these drugs, the ‘drug spillover.’”

For each TKI, there is a signature describing the kinases each drug fully or partially inhibits. Dr Tan and his colleagues combined these kinase inhibition signatures with the results of high-throughput screening. They used the Genomics of Drug Sensitivity in Cancer database to determine which TKIs have already proven active against which cancer cell lines.

The result is KAR, which does 2 things. For any cancer cell line, the program ranks the kinases that are most important to the growth of the disease. Then, the program recommends the combination of existing TKIs that is likely to do the most good against the implicated kinases.

Dr Tan and his colleagues tested KAR using samples from 151 leukemia patients and found that, among the kinases analyzed, FLT3 had the highest variance in sensitivity to TKIs.

But EPHA5, EPHA3, and BTK were the kinases most commonly associated with drug sensitivity. They had significant associations in 72%, 58%, and 54% of the patient samples, respectively.

The researchers said the frequency of BTK dependence they observed is interesting given the fact that the BTK inhibitor ibrutinib produced favorable results in a phase 1b/2 trial of patients with chronic lymphocytic leukemia (CLL). The progression-free survival rate at 26 months was 75% in that trial.

Dr Tan and his colleagues said this was consistent with their findings, which showed that 70% of CLL patient data had a significant association between BTK inhibition and drug sensitivity.

The researchers also found that KAR could predict TKI sensitivity in 21 lung cancer cell lines. In addition, the tool was able to recommend a combination of TKIs that hindered proliferation in the lung cancer cell line H1581. KAR suggested ponatinib and the experimental anticancer agent AZD8055, and experiments showed that these drugs synergistically reduced proliferation in H1581.

KAR is available for download on the Tan lab’s website.

Aik Choon Tan, PhD

Photo courtesy of the

University of Colorado

Researchers say they have developed a tool that allows us to determine which tyrosine kinase inhibitor (TKI) will be most effective against a certain type of cancer.

The tool, known as the Kinase Addiction Ranker (KAR), predicts the genetic abnormalities that are driving the cancer in any population of cells and chooses the best TKI or combination of TKIs to target these abnormalities.

The researchers described the tool in Bioinformatics.

“A lot of [TKIs] inhibit a lot more than what they’re supposed to inhibit,” said study author Aik Choon Tan, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.

“Maybe drug A was designed to inhibit kinase B, but it also inhibits kinase C and D as well. Our approach centers on exploiting the promiscuity of these drugs, the ‘drug spillover.’”

For each TKI, there is a signature describing the kinases each drug fully or partially inhibits. Dr Tan and his colleagues combined these kinase inhibition signatures with the results of high-throughput screening. They used the Genomics of Drug Sensitivity in Cancer database to determine which TKIs have already proven active against which cancer cell lines.

The result is KAR, which does 2 things. For any cancer cell line, the program ranks the kinases that are most important to the growth of the disease. Then, the program recommends the combination of existing TKIs that is likely to do the most good against the implicated kinases.

Dr Tan and his colleagues tested KAR using samples from 151 leukemia patients and found that, among the kinases analyzed, FLT3 had the highest variance in sensitivity to TKIs.

But EPHA5, EPHA3, and BTK were the kinases most commonly associated with drug sensitivity. They had significant associations in 72%, 58%, and 54% of the patient samples, respectively.

The researchers said the frequency of BTK dependence they observed is interesting given the fact that the BTK inhibitor ibrutinib produced favorable results in a phase 1b/2 trial of patients with chronic lymphocytic leukemia (CLL). The progression-free survival rate at 26 months was 75% in that trial.

Dr Tan and his colleagues said this was consistent with their findings, which showed that 70% of CLL patient data had a significant association between BTK inhibition and drug sensitivity.

The researchers also found that KAR could predict TKI sensitivity in 21 lung cancer cell lines. In addition, the tool was able to recommend a combination of TKIs that hindered proliferation in the lung cancer cell line H1581. KAR suggested ponatinib and the experimental anticancer agent AZD8055, and experiments showed that these drugs synergistically reduced proliferation in H1581.

KAR is available for download on the Tan lab’s website.

Red and white blood cells

A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.

In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).

Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.

Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.

Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.

“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.

“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”

For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.

Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.

Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.

Dosing and AEs

Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).

The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.

Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).

In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.

There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.

Clinical activity

The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).

Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.

Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.

Two of the 7 patients with MF had clinical improvement.

Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.

Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.

“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”

Red and white blood cells

A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.

In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).

Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.

Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.

Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.

“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.

“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”

For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.

Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.

Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.

Dosing and AEs

Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).

The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.

Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).

In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.

There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.

Clinical activity

The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).

Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.

Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.

Two of the 7 patients with MF had clinical improvement.

Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.

Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.

“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”

Red and white blood cells

A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.

In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).

Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.

Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.

Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.

“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.

“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”

For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.

Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.

Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.

Dosing and AEs

Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).

The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.

Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).

In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.

There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.

Clinical activity

The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).

Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.

Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.

Two of the 7 patients with MF had clinical improvement.

Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.

Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.

“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”

In vitro fertilization

Image courtesy of NHS

Young patients with cancer, particularly females, may be uninformed about their options for preserving fertility, according to a study published in Cancer.

The research showed that males were both more likely to have discussed fertility preservation with their physicians and more likely to have taken steps to preserve fertility.

Other factors such as education and insurance status also appeared to have an impact on fertility preservation.

Margarett Shnorhavorian, MD, of the University of Washington in Seattle, and her colleagues conducted this research.

The team enlisted 459 adolescents and young adults who were diagnosed with cancer in 2007 or 2008, asking them to complete questionnaires on fertility preservation.

Eighty percent of males and 74% of females said they had been told that cancer therapy might affect their fertility. For females, multivariable analysis revealed no significant factors associated with this discussion.

However, multivariable analysis showed that males with an unknown treatment fertility risk were more likely to be uninformed of the potential risk (odds ratio [OR]= 2.73; 95% CI, 1.09-6.86), as were males who did not consult a medical oncologist (OR=2.28; 95% CI, 1.03-5.00).

Twenty-nine percent of males and 56.3% of females said they did not discuss fertility preservation with their doctors before they began cancer treatment. Males raising children younger than 18 were more likely than males without children to miss out on the discussion (OR=2.45; 95% CI, 1.24-4.85).

Males were also more likely to miss the discussion if they had a treatment fertility risk classified as “none/low” rather than “intermediate/high” (OR=3.39; 95% CI, 1.60-7.16) and if they had no insurance or government insurance rather than private insurance (OR=2.91; 95% CI, 1.41-5.97).

Males diagnosed in 2008 were less likely than those diagnosed in 2007 to miss out on the discussion (OR=0.43; 95% CI, 0.20-0.80).

Females raising children under 18 were more likely than females without children to say they did not discuss fertility preservation with their doctors (OR=3.38; 95% CI, 1.43-8.02). Females without private insurance were more likely to miss the discussion as well (OR=5.46; 95% CI, 1.59-18.72).

Females diagnosed in 2008 were less likely to miss the discussion than those diagnosed in 2007 (OR=0.36; 95% CI, 0.15-0.85).

Sixty-nine percent of males and 93.2% of females said they did not make fertility preservation arrangements. Men were more likely to lack arrangements if they were raising children younger than 18 years (OR=3.53; 95% CI, 1.63-7.65) or had less than a college degree (OR, 1.98; 95% CI, 1.00-3.97).

The researchers did not conduct a multivariable analysis for women because so few women made arrangements for fertility preservation.

“The access and health-related reasons for not making arrangements for fertility preservation reported by participants in this study further highlight the need for decreased cost, improved insurance coverage, and partnerships between cancer healthcare providers and fertility experts to develop strategies that increase awareness of fertility preservation options and decrease delays in cancer therapy as fertility preservation for adolescent and young adult cancer patients improves,” Dr Shnorhavorian concluded.

In vitro fertilization

Image courtesy of NHS

Young patients with cancer, particularly females, may be uninformed about their options for preserving fertility, according to a study published in Cancer.

The research showed that males were both more likely to have discussed fertility preservation with their physicians and more likely to have taken steps to preserve fertility.

Other factors such as education and insurance status also appeared to have an impact on fertility preservation.

Margarett Shnorhavorian, MD, of the University of Washington in Seattle, and her colleagues conducted this research.

The team enlisted 459 adolescents and young adults who were diagnosed with cancer in 2007 or 2008, asking them to complete questionnaires on fertility preservation.

Eighty percent of males and 74% of females said they had been told that cancer therapy might affect their fertility. For females, multivariable analysis revealed no significant factors associated with this discussion.

However, multivariable analysis showed that males with an unknown treatment fertility risk were more likely to be uninformed of the potential risk (odds ratio [OR]= 2.73; 95% CI, 1.09-6.86), as were males who did not consult a medical oncologist (OR=2.28; 95% CI, 1.03-5.00).

Twenty-nine percent of males and 56.3% of females said they did not discuss fertility preservation with their doctors before they began cancer treatment. Males raising children younger than 18 were more likely than males without children to miss out on the discussion (OR=2.45; 95% CI, 1.24-4.85).

Males were also more likely to miss the discussion if they had a treatment fertility risk classified as “none/low” rather than “intermediate/high” (OR=3.39; 95% CI, 1.60-7.16) and if they had no insurance or government insurance rather than private insurance (OR=2.91; 95% CI, 1.41-5.97).

Males diagnosed in 2008 were less likely than those diagnosed in 2007 to miss out on the discussion (OR=0.43; 95% CI, 0.20-0.80).

Females raising children under 18 were more likely than females without children to say they did not discuss fertility preservation with their doctors (OR=3.38; 95% CI, 1.43-8.02). Females without private insurance were more likely to miss the discussion as well (OR=5.46; 95% CI, 1.59-18.72).

Females diagnosed in 2008 were less likely to miss the discussion than those diagnosed in 2007 (OR=0.36; 95% CI, 0.15-0.85).

Sixty-nine percent of males and 93.2% of females said they did not make fertility preservation arrangements. Men were more likely to lack arrangements if they were raising children younger than 18 years (OR=3.53; 95% CI, 1.63-7.65) or had less than a college degree (OR, 1.98; 95% CI, 1.00-3.97).

The researchers did not conduct a multivariable analysis for women because so few women made arrangements for fertility preservation.

“The access and health-related reasons for not making arrangements for fertility preservation reported by participants in this study further highlight the need for decreased cost, improved insurance coverage, and partnerships between cancer healthcare providers and fertility experts to develop strategies that increase awareness of fertility preservation options and decrease delays in cancer therapy as fertility preservation for adolescent and young adult cancer patients improves,” Dr Shnorhavorian concluded.

In vitro fertilization

Image courtesy of NHS

Young patients with cancer, particularly females, may be uninformed about their options for preserving fertility, according to a study published in Cancer.

The research showed that males were both more likely to have discussed fertility preservation with their physicians and more likely to have taken steps to preserve fertility.

Other factors such as education and insurance status also appeared to have an impact on fertility preservation.

Margarett Shnorhavorian, MD, of the University of Washington in Seattle, and her colleagues conducted this research.

The team enlisted 459 adolescents and young adults who were diagnosed with cancer in 2007 or 2008, asking them to complete questionnaires on fertility preservation.

Eighty percent of males and 74% of females said they had been told that cancer therapy might affect their fertility. For females, multivariable analysis revealed no significant factors associated with this discussion.

However, multivariable analysis showed that males with an unknown treatment fertility risk were more likely to be uninformed of the potential risk (odds ratio [OR]= 2.73; 95% CI, 1.09-6.86), as were males who did not consult a medical oncologist (OR=2.28; 95% CI, 1.03-5.00).

Twenty-nine percent of males and 56.3% of females said they did not discuss fertility preservation with their doctors before they began cancer treatment. Males raising children younger than 18 were more likely than males without children to miss out on the discussion (OR=2.45; 95% CI, 1.24-4.85).

Males were also more likely to miss the discussion if they had a treatment fertility risk classified as “none/low” rather than “intermediate/high” (OR=3.39; 95% CI, 1.60-7.16) and if they had no insurance or government insurance rather than private insurance (OR=2.91; 95% CI, 1.41-5.97).

Males diagnosed in 2008 were less likely than those diagnosed in 2007 to miss out on the discussion (OR=0.43; 95% CI, 0.20-0.80).

Females raising children under 18 were more likely than females without children to say they did not discuss fertility preservation with their doctors (OR=3.38; 95% CI, 1.43-8.02). Females without private insurance were more likely to miss the discussion as well (OR=5.46; 95% CI, 1.59-18.72).

Females diagnosed in 2008 were less likely to miss the discussion than those diagnosed in 2007 (OR=0.36; 95% CI, 0.15-0.85).

Sixty-nine percent of males and 93.2% of females said they did not make fertility preservation arrangements. Men were more likely to lack arrangements if they were raising children younger than 18 years (OR=3.53; 95% CI, 1.63-7.65) or had less than a college degree (OR, 1.98; 95% CI, 1.00-3.97).

The researchers did not conduct a multivariable analysis for women because so few women made arrangements for fertility preservation.

“The access and health-related reasons for not making arrangements for fertility preservation reported by participants in this study further highlight the need for decreased cost, improved insurance coverage, and partnerships between cancer healthcare providers and fertility experts to develop strategies that increase awareness of fertility preservation options and decrease delays in cancer therapy as fertility preservation for adolescent and young adult cancer patients improves,” Dr Shnorhavorian concluded.

Lab mice

Photo by Aaron Logan

Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).

Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.

However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.

The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.

Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.

The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.

The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.

After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.

The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.

On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.

The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.

A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.

“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.

Lab mice

Photo by Aaron Logan

Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).

Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.

However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.

The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.

Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.

The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.

The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.

After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.

The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.

On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.

The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.

A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.

“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.

Lab mice

Photo by Aaron Logan

Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).

Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.

However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.

The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.

Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.

The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.

The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.

After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.

The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.

On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.

The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.

A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.

“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.

Cord blood for transplant

Photo courtesy of NHS

Investigators have reported favorable results of allogeneic hematopoietic stem cell transplant (HSCT) in a small study of patients with juvenile myelomonocytic leukemia (JMML).

The team said the positive outcomes may be a result of conditioning with busulfan and melphalan (BuMel) or the conventional-dose chemotherapy some patients received before HSCT.

Regardless, all 7 patients studied are in remission at more than 1 year of follow-up.

“The lack of transplant-related mortality in the group of children we studied . . . suggests that BuMel may represent a successful HSCT high-dose chemotherapy regimen,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“It is also possible that administering conventional-dose chemotherapy before HSCT to patients with more progressive disease may have contributed to the improved outcomes.”

Dr Abdel-Azim and his colleagues described this research in a letter to Blood.

Conventional chemo and transplant

The investigators retrospectively analyzed 7 JMML patients with a median age of 2.6 years at HSCT.

Five patients received conventional-dose chemotherapy before transplant. All of these patients received mercaptopurine. One received hydroxyurea as well, and another patient received fludarabine, cytarabine, and cis-retinoic acid.

As for transplant, 2 patients received a 10/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched unrelated bone marrow graft, and 3 patients received cord blood grafts.

The median total nucleated cell count was 4.2 × 10⁸ cells/kg, and the median CD34 cell dose was 3.3 × 10⁶ cells/kg.

Conditioning and GVHD prophylaxis

All 7 patients received backbone conditioning with BuMel: Bu at 1 mg/kg dose every 6 hours intravenously on days −8 to −5 (with therapeutic drug monitoring to achieve overall concentration steady state [CSS] of 800-1000 ng/mL) and Mel at 45 mg/m² per day intravenously on days −4 to −2.

The median Bu CSS and area under the curve were 884 µg/L (range, 560-1096) and 1293 µmol/L-minute (range, 819-1601), respectively.

The patient with a 9/10 HLA-matched related graft received BuMel and fludarabine at 35 mg/m² per day intravenously on days −7 to −4.

The patient with the 9/10 HLA-matched unrelated graft received BuMel and alemtuzumab at 12 mg/m² intravenously on day −10 and 20 mg/m² on day −9, with methylprednisolone at 2 mg/kg per day in divided doses during the alemtuzumab infusion.

The patients who received cord blood grafts received BuMel and rabbit antithymocyte globulin at 2.5 mg/kg per day intravenously on days −4 to −1. They also received methylprednisolone at 2 mg/kg per day in divided doses during antithymocyte globulin infusion, then tapered over 6 weeks.

All patients received tacrolimus as graft-vs-host disease (GVHD) prophylaxis. Patients who received bone marrow grafts also received methotrexate at 5 mg/m² on days 3, 6, and 11.

Outcomes

The median time to neutrophil engraftment (≥500/mm³) was 20 days, and the median time to platelet engraftment (≥20 000/mm³) was 36 days.

Six patients (85.7%) achieved predominant (>95%) donor hematopoietic stem cell engraftment.

One patient who received a cord blood graft had autologous recovery at day 54. She went on to receive a related haploidentical HSCT on day 105. One hundred days later, she is in remission, with predominant donor chimerism.

The patient who received the 9/10 HLA-matched related graft developed grade 4 acute GVHD, followed by severe chronic GVHD that required bowel resection.

This patient and one of the patients who received a 10/10 HLA-matched related graft developed severe sinusoidal obstructive syndrome, which resolved with supportive care.

At a median follow-up of 25.3 months (range, 6-99.3), all 7 patients are in remission.

The investigators said their target Bu CSS may have contributed to the improved outcomes they observed, or pre-HSCT chemotherapy may have been a contributing factor. A prospective clinical trial could provide answers.

Cord blood for transplant

Photo courtesy of NHS

Investigators have reported favorable results of allogeneic hematopoietic stem cell transplant (HSCT) in a small study of patients with juvenile myelomonocytic leukemia (JMML).

The team said the positive outcomes may be a result of conditioning with busulfan and melphalan (BuMel) or the conventional-dose chemotherapy some patients received before HSCT.

Regardless, all 7 patients studied are in remission at more than 1 year of follow-up.

“The lack of transplant-related mortality in the group of children we studied . . . suggests that BuMel may represent a successful HSCT high-dose chemotherapy regimen,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“It is also possible that administering conventional-dose chemotherapy before HSCT to patients with more progressive disease may have contributed to the improved outcomes.”

Dr Abdel-Azim and his colleagues described this research in a letter to Blood.

Conventional chemo and transplant

The investigators retrospectively analyzed 7 JMML patients with a median age of 2.6 years at HSCT.

Five patients received conventional-dose chemotherapy before transplant. All of these patients received mercaptopurine. One received hydroxyurea as well, and another patient received fludarabine, cytarabine, and cis-retinoic acid.

As for transplant, 2 patients received a 10/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched unrelated bone marrow graft, and 3 patients received cord blood grafts.

The median total nucleated cell count was 4.2 × 10⁸ cells/kg, and the median CD34 cell dose was 3.3 × 10⁶ cells/kg.

Conditioning and GVHD prophylaxis

All 7 patients received backbone conditioning with BuMel: Bu at 1 mg/kg dose every 6 hours intravenously on days −8 to −5 (with therapeutic drug monitoring to achieve overall concentration steady state [CSS] of 800-1000 ng/mL) and Mel at 45 mg/m² per day intravenously on days −4 to −2.

The median Bu CSS and area under the curve were 884 µg/L (range, 560-1096) and 1293 µmol/L-minute (range, 819-1601), respectively.

The patient with a 9/10 HLA-matched related graft received BuMel and fludarabine at 35 mg/m² per day intravenously on days −7 to −4.

The patient with the 9/10 HLA-matched unrelated graft received BuMel and alemtuzumab at 12 mg/m² intravenously on day −10 and 20 mg/m² on day −9, with methylprednisolone at 2 mg/kg per day in divided doses during the alemtuzumab infusion.

The patients who received cord blood grafts received BuMel and rabbit antithymocyte globulin at 2.5 mg/kg per day intravenously on days −4 to −1. They also received methylprednisolone at 2 mg/kg per day in divided doses during antithymocyte globulin infusion, then tapered over 6 weeks.

All patients received tacrolimus as graft-vs-host disease (GVHD) prophylaxis. Patients who received bone marrow grafts also received methotrexate at 5 mg/m² on days 3, 6, and 11.

Outcomes

The median time to neutrophil engraftment (≥500/mm³) was 20 days, and the median time to platelet engraftment (≥20 000/mm³) was 36 days.

Six patients (85.7%) achieved predominant (>95%) donor hematopoietic stem cell engraftment.

One patient who received a cord blood graft had autologous recovery at day 54. She went on to receive a related haploidentical HSCT on day 105. One hundred days later, she is in remission, with predominant donor chimerism.

The patient who received the 9/10 HLA-matched related graft developed grade 4 acute GVHD, followed by severe chronic GVHD that required bowel resection.

This patient and one of the patients who received a 10/10 HLA-matched related graft developed severe sinusoidal obstructive syndrome, which resolved with supportive care.

At a median follow-up of 25.3 months (range, 6-99.3), all 7 patients are in remission.

The investigators said their target Bu CSS may have contributed to the improved outcomes they observed, or pre-HSCT chemotherapy may have been a contributing factor. A prospective clinical trial could provide answers.

Cord blood for transplant

Photo courtesy of NHS

Investigators have reported favorable results of allogeneic hematopoietic stem cell transplant (HSCT) in a small study of patients with juvenile myelomonocytic leukemia (JMML).

The team said the positive outcomes may be a result of conditioning with busulfan and melphalan (BuMel) or the conventional-dose chemotherapy some patients received before HSCT.

Regardless, all 7 patients studied are in remission at more than 1 year of follow-up.

“The lack of transplant-related mortality in the group of children we studied . . . suggests that BuMel may represent a successful HSCT high-dose chemotherapy regimen,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“It is also possible that administering conventional-dose chemotherapy before HSCT to patients with more progressive disease may have contributed to the improved outcomes.”

Dr Abdel-Azim and his colleagues described this research in a letter to Blood.

Conventional chemo and transplant

The investigators retrospectively analyzed 7 JMML patients with a median age of 2.6 years at HSCT.

Five patients received conventional-dose chemotherapy before transplant. All of these patients received mercaptopurine. One received hydroxyurea as well, and another patient received fludarabine, cytarabine, and cis-retinoic acid.

As for transplant, 2 patients received a 10/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched unrelated bone marrow graft, and 3 patients received cord blood grafts.

The median total nucleated cell count was 4.2 × 10⁸ cells/kg, and the median CD34 cell dose was 3.3 × 10⁶ cells/kg.

Conditioning and GVHD prophylaxis

All 7 patients received backbone conditioning with BuMel: Bu at 1 mg/kg dose every 6 hours intravenously on days −8 to −5 (with therapeutic drug monitoring to achieve overall concentration steady state [CSS] of 800-1000 ng/mL) and Mel at 45 mg/m² per day intravenously on days −4 to −2.

The median Bu CSS and area under the curve were 884 µg/L (range, 560-1096) and 1293 µmol/L-minute (range, 819-1601), respectively.

The patient with a 9/10 HLA-matched related graft received BuMel and fludarabine at 35 mg/m² per day intravenously on days −7 to −4.

The patient with the 9/10 HLA-matched unrelated graft received BuMel and alemtuzumab at 12 mg/m² intravenously on day −10 and 20 mg/m² on day −9, with methylprednisolone at 2 mg/kg per day in divided doses during the alemtuzumab infusion.

The patients who received cord blood grafts received BuMel and rabbit antithymocyte globulin at 2.5 mg/kg per day intravenously on days −4 to −1. They also received methylprednisolone at 2 mg/kg per day in divided doses during antithymocyte globulin infusion, then tapered over 6 weeks.

All patients received tacrolimus as graft-vs-host disease (GVHD) prophylaxis. Patients who received bone marrow grafts also received methotrexate at 5 mg/m² on days 3, 6, and 11.

Outcomes

The median time to neutrophil engraftment (≥500/mm³) was 20 days, and the median time to platelet engraftment (≥20 000/mm³) was 36 days.

Six patients (85.7%) achieved predominant (>95%) donor hematopoietic stem cell engraftment.

One patient who received a cord blood graft had autologous recovery at day 54. She went on to receive a related haploidentical HSCT on day 105. One hundred days later, she is in remission, with predominant donor chimerism.

The patient who received the 9/10 HLA-matched related graft developed grade 4 acute GVHD, followed by severe chronic GVHD that required bowel resection.

This patient and one of the patients who received a 10/10 HLA-matched related graft developed severe sinusoidal obstructive syndrome, which resolved with supportive care.

At a median follow-up of 25.3 months (range, 6-99.3), all 7 patients are in remission.

The investigators said their target Bu CSS may have contributed to the improved outcomes they observed, or pre-HSCT chemotherapy may have been a contributing factor. A prospective clinical trial could provide answers.

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.