Although mesothelioma is generally regarded to be a rare cancer, it appears to be getting more common. More than 2,300 people are diagnosed with the disease every year in the UK alone, with approximately five-times as many cases in men as in women. According to Cancer Research UK, the number of cases of mesothelioma in the UK each year is expected to rise dramatically over the next 20 years because of the heavy use of asbestos in industry from the end of the second world war up until the mid-1970s. Mesothelioma in the chest (pleural mesothelioma; PM) is much more common than in the abdomen (peritoneal mesothelioma).
Recent work by Rosetta Genomics and New York University demonstrated the potential of miR-31, an miRNA that has recently been characterised as a suppressor of breast cancer metastases, to be used for the development of new therapies against mesothelioma and other cancers. In the study, published in the 12th May online edition of the Journal of Biological Chemistry (10.1074/jbc.M110.100354), cell lines derived from mesothelioma patients were found not to express miR-31. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion and clonogenicity of mesothelioma cells. The reintroduction of miR-31 suppressed cell cycle and inhibited expression of multiple factors involved in co-operative maintenance of DNA replication and cell cycle progression.
miRNAs, described as the body's master switches, hold significant potential for therapeutic applications, and have been shown to be highly-sensitive and specific biomarkers in recent work. Kenneth A Berlin, President and CEO of Rosetta, commented: "This latest publication is another demonstration of miRNAs' potential role in cancer therapeutics and details the significant impact a single miRNA can have on disease course." Using its diagnostic tests for cancer, and robust and diverse miRNA-based product pipeline, Rosetta plans to continue its research in this field by harnessing the power of miRNAs.
A further development in mesothelioma also occurred in May, as MolMed received clearance from the FDA for the IND application filed to initiate a Phase III trial of its investigational antitumour drug, NGR-hTNF, for the treatment of malignant PM (MPM). The study, NGR015, is a pivotal randomised, double-blind, placebo-controlled, international, multi-centre, Phase III trial, expecting to enrol adult patients affected by MPM with disease progressing after chemotherapy. The main endpoint of the trial is overall survival; secondary endpoints include progression-free survival, disease control rate, safety and patient quality of life. Based on the positive results of a multi-centre, Phase II study, this Phase III trial is optimally designed to investigate the full therapeutic potential of NGR-hTNF in the treatment of MPM. If positive data are yielded from this study, NGR-hTNF may represent a novel treatment option for malignant mesothelioma.
Alice Rossiter
Editor, Cancer Drug News
Friday, May 28, 2010
Friday, May 14, 2010
New findings could advance fight against BC
Recent findings by scientists could help advance the fight against breast cancer (BC). A team at the University of Kentucky (UoK) Markey Cancer Center has identified a key molecular mechanism in BC that enables tumour cells to metastasise, while a separate study has uncovered five new regions of the genome that increase a woman's risk of developing the disease by between 6 and 16 per cent.
The work conducted by the UoK could lead to new lines of research aimed at developing treatments for metastatic BC (MBC). The research, published in the 13th April online issue of The EMBO Journal (10.1038/emboj.2010.63), focused on the process by which tumour cells stop clinging to other cells and become motile. The increased motility of tumour cells at the initial step of metastasis is similar to epithelial-mesenchymal transition (EMT). In all EMT processes, cells lose the expression of E-cadherin, which functions as a "molecular glue" that attaches cells to one another. The team explained that when E-cadherin is broken down, tumour cells start to migrate and spread throughout the body.
A protein called Snail acts as a master switch in the cell's nucleus to suppress E-cadherin expression and induce EMT in the cell. Agents that can disrupt the interaction of Snail are thought to have great therapeutic potential for treating MBC. Leading on from these findings, the scientists at the UoK are keen to develop drugs that can treat metastatic cancer.
Separately, a study funded by Cancer Research UK (CRUK) and the Wellcome Trust has found five new regions of the genome that increase a woman's risk of developing BC by between 6 and 16 per cent. As more of these low-risk sites are found, scientists believe that it may be possible to create tests for a combination of them that together significantly increase risk, which could ultimately help doctors to make decisions about prevention, diagnosis and treatment for women who are more likely to get BC.
The scientists scanned the entire genetic code of over 4,000 women with BC and a family history of the disease for genetic variations that appeared more often compared to healthy women. They then tested the most promising regions in over 12,000 women with BC and 12,000 women without the disease in an international collaboration. Although the results now take the total number of gene regions linked to the risk of BC to 18, scientists are still unsure which genes are causing this increased risk. Lead author, Professor Doug Easton, director of CRUK's Genetic Epidemiology Unit at the University of Cambridge, commented: "While each of these sites have a small impact on breast cancer risk, by finding more of these genes, we may be able to develop a test that can predict more reliably a woman's risk of developing breast cancer."
Alice Rossiter - Editor, Cancer Drug News
The work conducted by the UoK could lead to new lines of research aimed at developing treatments for metastatic BC (MBC). The research, published in the 13th April online issue of The EMBO Journal (10.1038/emboj.2010.63), focused on the process by which tumour cells stop clinging to other cells and become motile. The increased motility of tumour cells at the initial step of metastasis is similar to epithelial-mesenchymal transition (EMT). In all EMT processes, cells lose the expression of E-cadherin, which functions as a "molecular glue" that attaches cells to one another. The team explained that when E-cadherin is broken down, tumour cells start to migrate and spread throughout the body.
A protein called Snail acts as a master switch in the cell's nucleus to suppress E-cadherin expression and induce EMT in the cell. Agents that can disrupt the interaction of Snail are thought to have great therapeutic potential for treating MBC. Leading on from these findings, the scientists at the UoK are keen to develop drugs that can treat metastatic cancer.
Separately, a study funded by Cancer Research UK (CRUK) and the Wellcome Trust has found five new regions of the genome that increase a woman's risk of developing BC by between 6 and 16 per cent. As more of these low-risk sites are found, scientists believe that it may be possible to create tests for a combination of them that together significantly increase risk, which could ultimately help doctors to make decisions about prevention, diagnosis and treatment for women who are more likely to get BC.
The scientists scanned the entire genetic code of over 4,000 women with BC and a family history of the disease for genetic variations that appeared more often compared to healthy women. They then tested the most promising regions in over 12,000 women with BC and 12,000 women without the disease in an international collaboration. Although the results now take the total number of gene regions linked to the risk of BC to 18, scientists are still unsure which genes are causing this increased risk. Lead author, Professor Doug Easton, director of CRUK's Genetic Epidemiology Unit at the University of Cambridge, commented: "While each of these sites have a small impact on breast cancer risk, by finding more of these genes, we may be able to develop a test that can predict more reliably a woman's risk of developing breast cancer."
Alice Rossiter - Editor, Cancer Drug News
Wednesday, April 21, 2010
Neutropenia still prevalent despite drug availability
According to findings from a pan-European patient and nurse survey presented at the 7th Annual European Oncology Nursing Society (EONS) Spring Convention, held from 15th to 16th April, in the Hague, the Netherlands, 30 per cent of patients surveyed experienced an infection as a result of chemotherapy (CT), 45 per cent of which were associated with neutropenia or febrile neutropenia (FN). These results suggest that despite the widespread availability of prophylactic treatments, a significant number of cancer patients continue to be affected by neutropenia and its consequences.
The survey, which was sponsored by Amgen, was conducted by the EONS in nine European countries to explore current perceptions and issues relating to cancer therapy and infection, specifically neutropenia and FN. The survey found that 57 per cent of patients with an infection required hospitalisation, whilst 37 per cent had to have their CT delayed or changed as a result of neutropenia, infection or FN. More than nine out of ten nurses questioned agreed that preventing infections, such as FN, is important to achieve a successful outcome for patients undergoing CT. Kay Leonard, EONS Board Member, commented: "The survey results suggest that the risk of neutropenia and the impact this can have on patients' clinical care and quality of life must be taken even more seriously...it is important to ensure patients are receiving the most effective and appropriate prophylactic therapies as early as possible to help achieve positive treatment outcomes and prevent related complications before they develop."
Treatments are available to prevent and manage CT-induced infections, and significant progress has been made in the development of proactive therapies to help manage side effects of CT. For example, in March, the European Medicines Agency's CHMP adopted a positive opinion recommending the granting of a marketing authorisation for Hospira's Nivestim (filgrastim), a recombinant human G-CSF intended for the treatment of neutropenia. This medicine has been shown to be similar to Amgen's Neupogen (filgrastim), which is already authorised in the EU for the same indication and as one of the company's major products, achieved 2009 sales of US$1,288 million. Further, Sandoz' (Novartis) Zarzio (filgrastim) was launched in the UK last year and has been shown to have an efficacy and safety profile comparable with Neupogen, but is 10 per cent less expensive.
Many recombinant human G-CSFs are available to treat or prevent neutropenia, and therefore reduce associated complications. This is reflected in 54 per cent of nurse survey respondents who confirmed using G-CSFs prophylactically to prevent FN in patients receiving CT. An additional 27 per cent of nurses reported using both G-CSFs and antibiotics, however, 85 per cent of nurse respondents expressed concerns regarding patient compliance to treatment.
Moreover, it was reported by patients in the survey that access to and provision of treatments that prevent infection varies widely across Europe. A significant number of patient respondents did not appear to fully understand their risk of developing FN, which suggests a need for improvement in communication between patients and healthcare providers.
Alice Rossiter
Editor, Cancer Drug News
The survey, which was sponsored by Amgen, was conducted by the EONS in nine European countries to explore current perceptions and issues relating to cancer therapy and infection, specifically neutropenia and FN. The survey found that 57 per cent of patients with an infection required hospitalisation, whilst 37 per cent had to have their CT delayed or changed as a result of neutropenia, infection or FN. More than nine out of ten nurses questioned agreed that preventing infections, such as FN, is important to achieve a successful outcome for patients undergoing CT. Kay Leonard, EONS Board Member, commented: "The survey results suggest that the risk of neutropenia and the impact this can have on patients' clinical care and quality of life must be taken even more seriously...it is important to ensure patients are receiving the most effective and appropriate prophylactic therapies as early as possible to help achieve positive treatment outcomes and prevent related complications before they develop."
Treatments are available to prevent and manage CT-induced infections, and significant progress has been made in the development of proactive therapies to help manage side effects of CT. For example, in March, the European Medicines Agency's CHMP adopted a positive opinion recommending the granting of a marketing authorisation for Hospira's Nivestim (filgrastim), a recombinant human G-CSF intended for the treatment of neutropenia. This medicine has been shown to be similar to Amgen's Neupogen (filgrastim), which is already authorised in the EU for the same indication and as one of the company's major products, achieved 2009 sales of US$1,288 million. Further, Sandoz' (Novartis) Zarzio (filgrastim) was launched in the UK last year and has been shown to have an efficacy and safety profile comparable with Neupogen, but is 10 per cent less expensive.
Many recombinant human G-CSFs are available to treat or prevent neutropenia, and therefore reduce associated complications. This is reflected in 54 per cent of nurse survey respondents who confirmed using G-CSFs prophylactically to prevent FN in patients receiving CT. An additional 27 per cent of nurses reported using both G-CSFs and antibiotics, however, 85 per cent of nurse respondents expressed concerns regarding patient compliance to treatment.
Moreover, it was reported by patients in the survey that access to and provision of treatments that prevent infection varies widely across Europe. A significant number of patient respondents did not appear to fully understand their risk of developing FN, which suggests a need for improvement in communication between patients and healthcare providers.
Alice Rossiter
Editor, Cancer Drug News
Friday, April 9, 2010
Skin cancer rates rapidly rising
In line with its launch of the 2010 SunSmart campaign, Cancer Research UK (CRUK) has revealed that people aged 60 to 79 years of age are now over five-times more likely to be diagnosed with malignant melanoma (MM) than their parents would have been 30 years ago.
Of all ages, this generation has seen the biggest increase in incidence rates of melanoma, rising from seven cases per 100,000 people in the mid-1970s to 36 cases per 100,000 today. This rise shows the impact that a shift in tanning behaviour has had on a whole generation of men and women who would have been in their 20s and 30s in the 1970s, when holidays in the sun became cheap and popular, and sunbeds arrived in the UK.
According to CRUK statistics, the most common kind of skin cancer is non-melanoma skin cancer. More than 75,000 cases are registered each year in the UK, but it is estimated that the actual number is at least 100,000. More than 10,400 cases of MM are diagnosed each year in the UK and more than 2,000 people a year die from the disease.
For men in their 60s and 70s, the rates of melanoma have risen most dramatically; they are over seven-times more likely to be diagnosed with the disease than in the 1970s. For men and women of all ages, melanoma incidence rates have quadrupled since the 1970s. This rise in incidence rates is expected to continue: by 2024, rates in people aged 60 to 79 are predicted to increase by one-third from current statistics. Caroline Cerny, SunSmart manager at CRUK, commented: "The battle against melanoma is far from won. Today, the problem threatens to get worse as teenagers continue to crave a tan on the beach and top it up cheaply on sunbeds."
CRUK also noted that there has been a large increase in the overall death rates. Over a similar period, they have more than doubled from 1.2 per 100,000 in 1971 to 2.6 per 100,000 in the UK in 2007. If melanoma death rates had stayed the same as they were in 1973, approximately 19,000 fewer people would have died from the disease.
Although the incidence rates are predicted to rise, there are currently many promising drugs in development for MM. Of particular note, Pain Therapeutics (PT) recently reported encouraging clinical data with PTI-188, an early-stage drug for MM. Although efficacy was not a primary endpoint, PT and its clinical investigators were encouraged by the number of melanoma tumours that had either stabilised or decreased in size after a single dose of PTI-188. Further, Vical recently completed enrolment of the planned 375 subjects in its multi-national, Phase III trial of Allovectin-7 in patients with MM. Allovectin-7 is a novel gene-based immunotherapeutic with a unique mechanism of action that is fundamentally different from currently-approved treatments and has the potential to be the first new primary treatment approved for MM in nearly 20 years.
Alice Rossiter
Editor, Cancer Drug News
Of all ages, this generation has seen the biggest increase in incidence rates of melanoma, rising from seven cases per 100,000 people in the mid-1970s to 36 cases per 100,000 today. This rise shows the impact that a shift in tanning behaviour has had on a whole generation of men and women who would have been in their 20s and 30s in the 1970s, when holidays in the sun became cheap and popular, and sunbeds arrived in the UK.
According to CRUK statistics, the most common kind of skin cancer is non-melanoma skin cancer. More than 75,000 cases are registered each year in the UK, but it is estimated that the actual number is at least 100,000. More than 10,400 cases of MM are diagnosed each year in the UK and more than 2,000 people a year die from the disease.
For men in their 60s and 70s, the rates of melanoma have risen most dramatically; they are over seven-times more likely to be diagnosed with the disease than in the 1970s. For men and women of all ages, melanoma incidence rates have quadrupled since the 1970s. This rise in incidence rates is expected to continue: by 2024, rates in people aged 60 to 79 are predicted to increase by one-third from current statistics. Caroline Cerny, SunSmart manager at CRUK, commented: "The battle against melanoma is far from won. Today, the problem threatens to get worse as teenagers continue to crave a tan on the beach and top it up cheaply on sunbeds."
CRUK also noted that there has been a large increase in the overall death rates. Over a similar period, they have more than doubled from 1.2 per 100,000 in 1971 to 2.6 per 100,000 in the UK in 2007. If melanoma death rates had stayed the same as they were in 1973, approximately 19,000 fewer people would have died from the disease.
Although the incidence rates are predicted to rise, there are currently many promising drugs in development for MM. Of particular note, Pain Therapeutics (PT) recently reported encouraging clinical data with PTI-188, an early-stage drug for MM. Although efficacy was not a primary endpoint, PT and its clinical investigators were encouraged by the number of melanoma tumours that had either stabilised or decreased in size after a single dose of PTI-188. Further, Vical recently completed enrolment of the planned 375 subjects in its multi-national, Phase III trial of Allovectin-7 in patients with MM. Allovectin-7 is a novel gene-based immunotherapeutic with a unique mechanism of action that is fundamentally different from currently-approved treatments and has the potential to be the first new primary treatment approved for MM in nearly 20 years.
Alice Rossiter
Editor, Cancer Drug News
Wednesday, March 10, 2010
HRT linked to LC risk
Women who take hormone replacement therapy (HRT) are at an increased risk of developing lung cancer (LC), new research by the Oregon Health and Science University suggests. As published in the 16th February online edition of the Journal of Clinical Oncology (10.1200/JCO.2009.25.9739), women aged 50 to 76 years who take oestrogen plus progestin (O+P) may have an increased risk of the disease.
According to the researchers, although the risk is duration-dependent, with women taking HRT for ten or more years at greatest risk of developing LC, an acceptable length of HRT has yet to be determined. However, it was noted that while the risk of developing LC for women using O+P for ten years or longer was approximately 50 per cent more than women not using HRT, this risk is small compared to the risk from smoking.
The scientists reviewed data collected from 2000 to 2002, and identified 36,588 peri- and postmenopausal participants aged 50 to 76 years who met their study criteria and followed them for six years. At the end of the observation period, December 2007, 344 of the participants had developed LC. After adjusting for smoking, age and other factors that affect the risk of the disease, the researchers determined that the use of O+P for ten or more years was associated with an increased risk for LC, compared with no use of HRT. They also found that the duration of use was associated with an advanced stage of cancer at diagnosis.
This research is not the first to highlight the risk of HRT use with LC. Scientists from the University of California, Los Angeles Medical Center previously reported that HRT using O+P increases the risk of death from LC. After the eight-year total follow-up from the study, published in the 20th September 2009 online edition of The Lancet (10.1016/S0140-6736(09)61526-9), the researchers found that more women died from LC in the combined HRT group than in the placebo group (73 compared to 40 deaths). In other words, women in the HRT group were 71 per cent more likely to die.
Further, it is not just an increased risk of LC that has been linked with HRT. According to results from a Stanford University study, published in the 5th February 2009 edition of the NEJM (2009;360:573-587), postmenopausal women who take combined O+P menopausal hormone therapy for at least five years double their annual risk of breast cancer. This multi-centre study also found that women on HRT can quickly reduce their risks of cancer simply by stopping the therapy.
Research such as this suggests that postmenopausal women, especially current smokers or long-term past smokers, should carefully consider these risks before initiating or continuing combined O+P use.
Alice Rossiter
Editor, Cancer Drug News
According to the researchers, although the risk is duration-dependent, with women taking HRT for ten or more years at greatest risk of developing LC, an acceptable length of HRT has yet to be determined. However, it was noted that while the risk of developing LC for women using O+P for ten years or longer was approximately 50 per cent more than women not using HRT, this risk is small compared to the risk from smoking.
The scientists reviewed data collected from 2000 to 2002, and identified 36,588 peri- and postmenopausal participants aged 50 to 76 years who met their study criteria and followed them for six years. At the end of the observation period, December 2007, 344 of the participants had developed LC. After adjusting for smoking, age and other factors that affect the risk of the disease, the researchers determined that the use of O+P for ten or more years was associated with an increased risk for LC, compared with no use of HRT. They also found that the duration of use was associated with an advanced stage of cancer at diagnosis.
This research is not the first to highlight the risk of HRT use with LC. Scientists from the University of California, Los Angeles Medical Center previously reported that HRT using O+P increases the risk of death from LC. After the eight-year total follow-up from the study, published in the 20th September 2009 online edition of The Lancet (10.1016/S0140-6736(09)61526-9), the researchers found that more women died from LC in the combined HRT group than in the placebo group (73 compared to 40 deaths). In other words, women in the HRT group were 71 per cent more likely to die.
Further, it is not just an increased risk of LC that has been linked with HRT. According to results from a Stanford University study, published in the 5th February 2009 edition of the NEJM (2009;360:573-587), postmenopausal women who take combined O+P menopausal hormone therapy for at least five years double their annual risk of breast cancer. This multi-centre study also found that women on HRT can quickly reduce their risks of cancer simply by stopping the therapy.
Research such as this suggests that postmenopausal women, especially current smokers or long-term past smokers, should carefully consider these risks before initiating or continuing combined O+P use.
Alice Rossiter
Editor, Cancer Drug News
Monday, March 1, 2010
Scientists establish link between deprivation and poor prognosis for BC
Deprivation has long been known to play a role in the development of a wide range of diseases, and to a higher risk of recurrence or death for patients diagnosed with a number of cancers. Previously, the effect of material deprivation on cancer survival in England and Wales was measured by Cancer Research UK, and results showed that cancer survival for adults is generally lower among patients in more deprived groups, even after allowance is made for the higher mortality from all causes of death in these groups.
The reasons for survival rates differing between breast cancer (BC) sufferers from poorer areas and more affluent areas has never been fully understood. Now, researchers from the University of Dundee have established a link between deprivation and the p53 gene, which explains why women from poorer backgrounds are less likely to survive BC. The team identified, for the first time, that p53 mutation in BC is associated with socio-economic deprivation, and that this helps account for the poorer prognosis for women from deprived communities.
As detailed in the 26th January online edition of the British Journal of Cancer (10.1038/sj.bjc.6605540), the scientists found that women from deprived backgrounds were more likely to experience a mutation of p53, and that this linked to higher relapse and mortality rates. According to the team, there are two ways that p53 mutations can come about; one is as a result of genetic predisposition and the other is as a result of lifestyle. Smoking, drinking and poor diet can lead to p53 mutations, and are more common in women from lower socio-economic groups, who are also more likely to experience a recurrence of the disease and to die as a result of BC.
The survey looked at a total of 246 women who underwent treatment for BC between 1997 and 2001. Examining frozen tissue, tests were carried out to determine p53 mutation status. Using the patients' postcodes, a deprivation score was attributed to each and examined against the outcome (full recovery, relapse, death). The team found that patients in the lowest socio-economic group were significantly more likely to have a relapse and die compared to those in more affluent categories. They also demonstrated that the worse survival and shorter disease-free interval in BC for the most deprived patients is associated with tumour p53 mutation.
This research demonstrates a strong link between p53 and deprivation, and then between p53 mutation and recurrence and death. The social application of this work would suggest that if deprivation can be targeted, then the deprived population would be less likely to have problems with their p53 gene and go on to develop BC. In reality, this is unlikely to be achieved, however, there has been numerous work surrounding the p53 protein: Cyclacel Pharmaceuticals' seliciclib (CYC202) is a promising anticancer agent that promotes cancer cell death by downregulation of key proteins, such as p53 and Mcl-1, associated with survival of cancer cells; and new research by Dartmouth Medical School has shown that p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer.
Alice Rossiter
Editor, Cancer Drug News
The reasons for survival rates differing between breast cancer (BC) sufferers from poorer areas and more affluent areas has never been fully understood. Now, researchers from the University of Dundee have established a link between deprivation and the p53 gene, which explains why women from poorer backgrounds are less likely to survive BC. The team identified, for the first time, that p53 mutation in BC is associated with socio-economic deprivation, and that this helps account for the poorer prognosis for women from deprived communities.
As detailed in the 26th January online edition of the British Journal of Cancer (10.1038/sj.bjc.6605540), the scientists found that women from deprived backgrounds were more likely to experience a mutation of p53, and that this linked to higher relapse and mortality rates. According to the team, there are two ways that p53 mutations can come about; one is as a result of genetic predisposition and the other is as a result of lifestyle. Smoking, drinking and poor diet can lead to p53 mutations, and are more common in women from lower socio-economic groups, who are also more likely to experience a recurrence of the disease and to die as a result of BC.
The survey looked at a total of 246 women who underwent treatment for BC between 1997 and 2001. Examining frozen tissue, tests were carried out to determine p53 mutation status. Using the patients' postcodes, a deprivation score was attributed to each and examined against the outcome (full recovery, relapse, death). The team found that patients in the lowest socio-economic group were significantly more likely to have a relapse and die compared to those in more affluent categories. They also demonstrated that the worse survival and shorter disease-free interval in BC for the most deprived patients is associated with tumour p53 mutation.
This research demonstrates a strong link between p53 and deprivation, and then between p53 mutation and recurrence and death. The social application of this work would suggest that if deprivation can be targeted, then the deprived population would be less likely to have problems with their p53 gene and go on to develop BC. In reality, this is unlikely to be achieved, however, there has been numerous work surrounding the p53 protein: Cyclacel Pharmaceuticals' seliciclib (CYC202) is a promising anticancer agent that promotes cancer cell death by downregulation of key proteins, such as p53 and Mcl-1, associated with survival of cancer cells; and new research by Dartmouth Medical School has shown that p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer.
Alice Rossiter
Editor, Cancer Drug News
Wednesday, February 17, 2010
Melanoma drugs potentially harmful to some patients
It is well known within the scientific community that the BRAF gene is faulty in approximately half of malignant melanomas and many other cancers, making it a suitable drug target. Drugs that block BRAF function in cells are already showing positive results in early clinical trials in melanoma. While the long-term effects of these drugs are not yet known, two new reports have suggested that these drugs may have unintended consequences in patients whose tumours lack mutations in the BRAF gene.
In separate studies, conducted by researchers in the US, from the Memorial Sloan-Kettering Cancer Center, and the UK, by the Institute of Cancer Research (ICR), scientists tested the drugs to better understand how they behave in cells, and found that they spurred the growth of some tumours. These preliminary findings raise the possibility that certain patients should not receive BRAF inhibitors, as they could make their cancers worse.
Based on these studies, it is thought that giving these drugs to patients whose tumours have normal copies of the BRAF gene could accelerate tumour growth. The findings suggest that physicians need to avoid treating patients who do not have certain genetic mutations, as they could potentially cause harm. The drugs primarily target a mutation in the BRAF gene, called V600E. Many, but not all of the patients enrolled in clinical trials of BRAF inhibitors have had this mutation in their tumours. The alteration is present in approximately half of all melanomas and it activates growth-promoting messages from the MAPK signalling pathway.
The new studies focused on tumours that had mutations elsewhere in the pathway. Both groups found that BRAF inhibitors can promote tumour growth in melanoma cells that lack the V600E mutation by activating other elements of the pathway. The researchers proposed several models that could potentially explain how a drug designed to inhibit the pathway could lead to its activation. The US study's first author, Dr Georgia Hatzivassiliou, of Genentech (Roche), noted that the new results, which were published in the 3rd February online edition of Nature (10.1038/nature08833), clearly indicate that the effects of BRAF inhibitors depend on the cellular context of a tumour cell. For instance, both research teams found that the drugs could activate BRAF signalling in melanoma tumours with mutations in the RAS gene, which is part of the BRAF pathway.
As reported by the ICR in the 22nd January issue of Cell (2010;140:209-221), the drugs fuelled rather than blocked the growth of melanoma cells with RAS mutations. Both studies concluded that a central player in the activation of the BRAF pathway was a protein, called CRAF, which is a close relative of BRAF. These findings provide a framework for understanding possible mechanisms of resistance to BRAF inhibitors and give researchers information about where to look in the signalling pathway.
This work has large implications, with every tumour being different; understanding more surrounding the biology of these tumours may allow scientists to develop better treatment options. Further, the impact of this research will enable physicians to target treatments more precisely to patients who will definitely benefit, and avoid treating those who will not. The financial impact of these findings is at present unknown, however, there are BRAF inhibitors currently in clinical development. Plexxikon's PLX4032 (also known as RG7204), which is in-licensed by Roche, is currently in an open-label, single-arm, Phase II trial, called BRIM2 (B-Raf Inhibitor in Melanoma), in previously-treated metastatic melanoma patients, and recently entered a pivotal Phase III trial, BRIM3, for the same indication.
Alice Rossiter
Editor, Cancer Drug News
In separate studies, conducted by researchers in the US, from the Memorial Sloan-Kettering Cancer Center, and the UK, by the Institute of Cancer Research (ICR), scientists tested the drugs to better understand how they behave in cells, and found that they spurred the growth of some tumours. These preliminary findings raise the possibility that certain patients should not receive BRAF inhibitors, as they could make their cancers worse.
Based on these studies, it is thought that giving these drugs to patients whose tumours have normal copies of the BRAF gene could accelerate tumour growth. The findings suggest that physicians need to avoid treating patients who do not have certain genetic mutations, as they could potentially cause harm. The drugs primarily target a mutation in the BRAF gene, called V600E. Many, but not all of the patients enrolled in clinical trials of BRAF inhibitors have had this mutation in their tumours. The alteration is present in approximately half of all melanomas and it activates growth-promoting messages from the MAPK signalling pathway.
The new studies focused on tumours that had mutations elsewhere in the pathway. Both groups found that BRAF inhibitors can promote tumour growth in melanoma cells that lack the V600E mutation by activating other elements of the pathway. The researchers proposed several models that could potentially explain how a drug designed to inhibit the pathway could lead to its activation. The US study's first author, Dr Georgia Hatzivassiliou, of Genentech (Roche), noted that the new results, which were published in the 3rd February online edition of Nature (10.1038/nature08833), clearly indicate that the effects of BRAF inhibitors depend on the cellular context of a tumour cell. For instance, both research teams found that the drugs could activate BRAF signalling in melanoma tumours with mutations in the RAS gene, which is part of the BRAF pathway.
As reported by the ICR in the 22nd January issue of Cell (2010;140:209-221), the drugs fuelled rather than blocked the growth of melanoma cells with RAS mutations. Both studies concluded that a central player in the activation of the BRAF pathway was a protein, called CRAF, which is a close relative of BRAF. These findings provide a framework for understanding possible mechanisms of resistance to BRAF inhibitors and give researchers information about where to look in the signalling pathway.
This work has large implications, with every tumour being different; understanding more surrounding the biology of these tumours may allow scientists to develop better treatment options. Further, the impact of this research will enable physicians to target treatments more precisely to patients who will definitely benefit, and avoid treating those who will not. The financial impact of these findings is at present unknown, however, there are BRAF inhibitors currently in clinical development. Plexxikon's PLX4032 (also known as RG7204), which is in-licensed by Roche, is currently in an open-label, single-arm, Phase II trial, called BRIM2 (B-Raf Inhibitor in Melanoma), in previously-treated metastatic melanoma patients, and recently entered a pivotal Phase III trial, BRIM3, for the same indication.
Alice Rossiter
Editor, Cancer Drug News
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