First Results of Largest Study of Genomes and Cancer Treatments Available
The first results as part of the largest study to correlate genetics with response to cancer drugs have now been made freely available on the Genomics of Drug Sensitivity in Cancer website.
Researchers based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, have provided the responses of 350 cancer samples to 18 anticancer therapeutics.
A patient’s response to anticancer treatment is partly determined by the combination of mutations in the patient’s cancer cells. The more this relationship is understood, the better the treatment can be targeted to a particular tumor. The overall idea of the current research is to use carefully collected data to provide a database for improving patient response during cancer treatment.
The coauthor of the Cancer Genome Project at the Wellcome Trust Sanger Institute, Cambridge, UK, Andy Futreal, said, “We know cancer is a genetic disease, it occurs in the main owing to mutations in critical target genes. Knowing what these cancer genes are allows us to ask the question ‘does the presence of one or more of them effect response to the therapeutics being developed, many of which are targeted either at the cancer genes themselves or at the pathways they are active in?’ This is a fundamental step in getting the most active drug in the most sensitive cancer – hopefully improving treatment response for patients.”
The researchers selected over 1000 genetically characterized cell lines that include many of the most common cancers. The researchers will take promising leads from these samples to be verified in clinical specimens: the findings will be used to design clinical studies in which treatment is based on a patient’s cancer mutation spectrum.
Futreal added, “For the next step, we will ramp up to screening the full 1000 cell lines and expand the drug sets… we will continue to develop analytical approaches to ask the questions of genetic context and the combined role of genome wide and specific copy number changes and expression in relation to response to anticancer agents. Further, we will sequence all genes in the cancer cell lines such that we will be positioned to ask the question of any new cancer gene or genes as they are identified by the large scale efforts underway to characterize the genomes of human cancer.”
The first results are said to provide a striking example of the power of this approach to identify genetic factors that determine drug response. They include sensitivity of melanoma, with activating mutations in the gene BRAF to molecular therapeutics targeting this protein, a therapeutic strategy that is currently being exploited in the clinical setting.
“It is very encouraging that we are able to clearly identify drug–gene interactions that are known to have clinical impact at an early stage in the study,” says Dr Ultan McDermott, Faculty Investigator at the Wellcome Trust Sanger Institute.
He added “We have already studied more gene mutation–drug interactions than any previous work but, more importantly, we are putting in place a mechanism to ensure rapid dissemination of our results to enable worldwide collaborative research. By ensuring that all the drug sensitivity data and correlative analysis are freely available in an easy-to-use website, we hope to enable and support the important work of the wider community of cancer researchers.”
Currently, we do not have sufficient understanding of the complexity of cancer–drug response to optimize treatment based on a person’s genome. It is hoped that through this study, the effectiveness of novel targeted cancer agents could be substantially improved by directing the treatment towards those patients that are most likely to benefit.
Sources: www.sanger.ac.uk/genetics/CGP/translation; www.medicalnewstoday.com/articles/194918.php
Oncologic Drugs Advisory Committee Recommends Withdrawing Approval for Bevacizumab Use in Breast Cancer Treatment
The Oncologic Drugs Advisory Committee (ODAC), a US FDA advisory panel, voted to recommend withdrawing the marketing authorization for bevacizumab (Avastin®; Genentech, Inc., CA, USA) for first-line use in metastatic breast cancer.
The original approval for bevacizumab was controversial as it was based on a single trial (E2100), which demonstrated that progression-free survival (PFS) was increased by 5.5 months in patients treated with bevacizumab and paclitaxel compared with paclitaxel alone (11.3 and 5.8 months, respectively), although no statistically significant overall survival advantage was observed.
The ODAC decision to recommend removing approval of the drug for this indication follows two further trials (AVADO and RIBBON 1), which demonstrated considerably shorter PFS advantage for the addition of bevacizumab (0.9 and 1.2 months, respectively) and no overall survival advantage. Given the known toxicity of bevacizumab, bleeding and gastrointestinal perforation, the panel felt that the risk–benefit ratio was not sufficiently favorable to recommend continued approval in this indication. The chair of the panel, Wyndham Wilson of the National Cancer Institute, MD, USA, pointed out that some of the side effects of bevacizumab can be fatal and stated that their first responsibly was to do no harm to patients. “We have to take into account risks, and there are definite risks,” he stated.
Gabriel Hortobagyi, Professor of Breast Medical Oncology at the MD Anderson Cancer Center, TX, USA, who attended the ODAC meeting as a consultant to Genentech, was disappointed with the decision. “Bevacizumab is clearly active in breast cancer, and there is more experience with this agent in metastatic breast cancer than with many, if not most, other agents evaluated for the metastatic breast cancer indication.” He stated, “Anecdotally, bevacizumab combinations can produce dramatic responses in individual patients, and it is my clinical impression that responses of such quality are seldom seen with the same chemotherapy programs without bevacizumab. As a frequent user of this agent, I have also found that it is very well tolerated by the great majority of patients; in very few do I need to modify dose or schedule, and in even fewer do I need to discontinue treatment because of toxicities.”
He concluded, “I am concerned, in part, because this recommendation might remove an important treatment option from patients with metastatic breast cancer. I am also concerned because ‘clinical benefit’ remains poorly defined. This precedent will set many drugs currently under development up for failure.”
Source: Medscape medical news: Will the FDA revoke bevacizumab’s approval for breast cancer? www.medscape.com/viewarticle/725509
Nanotechnology Used to Modify Chemotherapy Drug May Improve Cancer Treatment
A powerful chemotherapy drug has been modified using nanotechnology to make it less toxic to the kidneys. It is hoped that clinicians may be able to use the new drug at higher doses in cancer patients, making it more effective at combating tumors.
The first-line anticancer chemotherapy drug, cisplatin, is popular owing to it being relatively inexpensive and effective against a number of cancers; however, its use is limited owing to nephrotoxicity.
The drug works by delivering toxic platinum atoms to tumor sites. The problem lies in the fact that deposited platinum atoms are also toxic to the kidneys and accumulation in the kidney is undesirable.
Other chemotherapy drugs are used that do not deposit platinum as readily. This results in fewer toxic side effects but their effectiveness against tumors is also reduced.
An international collaboration of scientists, including Shiladitya Sengupta, Brigham and Women’s Hospital, MA, USA, has developed a larger cisplatin molecule that can be delivered effectively to a tumor but cannot be absorbed by the kidney.
The larger drug molecule was developed by binding many cisplatin molecules with a specially designed polymer that encouraged the whole molecule to form a ball shape, 100 nm in size. Particles more than 5 nm in size cannot pass into the kidney, so toxic build up of cisplatin in the kidney would be almost completed reduced. “It showed absolutely minimal toxicity to the kidney,” Sengupta explained.
The new compound has been found to be effective in delaying tumor growth in breast and lung cancers, as well as outperforming standard cisplatin in an ovarian cancer model. The research has yet to research human trials and lengthy testing will be required before the new molecule is ready for patient care.
The authors of the recent Proceedings of the National Academy of Sciences paper conclude that “Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.”
Source: Paraskar AS, Soni S, Chin KT et al.: Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy. Proc. Natl Acad. Sci. USA 107(28), 12435–12440 (2010).
Research Demonstrated That Genetically Modified T Cells Can Locate and Destroy Cancer in Mice
In research published in Proceedings of the National Academy of Sciences, scientists were able to watch in real time, as their creation of ‘tumor-seeking immune system cells’ located and destroyed cancer cells. Antoni Ribas, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), USA, explains, “We’re trying to genetically engineer the immune system to become a cancer killer and then image how the immune system operates at the same time.”
The research was carried out with melanomas that were grown in mice, and by arming lymphocytes with T-cell receptors (TCRs) using a viral vector, the lymphocytes became ‘specific killers’ of cancerous cells. By engineering the antigen-specific TCRs to specifically locate a tumor antigen on melanoma cell surfaces, the malignant cells are recognized as ‘enemies’.
The genetically engineered T cells were injected into the bloodstream of the mice and had located and started to attack the melanoma within 2–3 days. Scientists utilized genetic labeling with bioluminescence imaging and positron emitting tomography (PET) reporter genes to visualize the “distribution and antigen-specific tumor homing of TCR transgenic T cells”. The mice were monitored over 10 days to determine whether the cancer was actually being destroyed by the modified lymphocytes.
Ribas states, “We knew this approach of arming the lymphocytes with TCRs showed significant anti-tumor activity based on studies in humans. Now, by tracking the immune system’s reaction to cancer and imaging it in real time, we can project how the same process that succeeded in mice might behave in people.” If patients don’t respond well to this method, researches explained the possibility of checking whether the genetically engineered cells had or had not reached the tumor location, and whether they had functioned properly, using PET scanning.
Richard Koya, David Geffen School of Medicine, UCLA, USA, states, “The novelty of our work is that we were able to pack together the cancer-specific TCR and the PET reporter genes in a single vector and use it in mice with an intact immune system that closely resembles what we would see in real patients. We were also gladly surprised to see the targeted tumors literally melt away and disappear, underscoring the power of the combined approach of immune and gene therapy to control cancer.”
The time frame for locating and destroying cancerous cells in humans may potentially be longer and human studies of this method could begin in approximately 1 year. In their paper, the authors state that “This approach of TCR engineering and molecular imaging reporter gene labeling is directly translatable to humans and provides useful information on how to clinically develop this mode of therapy.”
Sources: Koya RC, Mok S, Comin-Anduix B et al.: Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. Proc. Natl Acad. Sci. USA 107(32), 14286–14291 (2010); UCLA Newsroom: http://newsroom.ucla.edu