Tag Archives: Targeted Therapies

ASCO 2011: Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors

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Cabozantinib (XL184) demonstrated high rates of disease control in patients with prostate, ovarian and liver cancers. The investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. 

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving cabozantinib (XL184) were highlighted today in the ASCO press briefing, as summarized below.

Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, and Can Shrink or Eliminate Bone Metastases 

Cabozantinib (XL184) – an oral inhibitor of MET and VEGFR2 kinases involved in the development and progression of many cancers – showed strong responses in patients with various advanced cancers in a phase II trial. The drug demonstrated particularly high rates of disease control for advanced prostate, ovarian and liver cancers, which are historically resistant to available therapies. The drug also fully or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Michael S. Gordon, M.D., President & Chief Executive Officer, Pinnacle Oncology Hematology.

“Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia,” said lead author Michael S. Gordon, M.D., a medical oncologist at Pinnacle Oncology Hematology located in Scottsdale, Arizona. “The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

To be eligible for the study, patients had to have advanced, progressive solid tumors, with or without bone metastases. Of 398 evaluable patients (of 483 enrolled in the trial), 39 percent had bone metastases at baseline. Patients received cabozantinib over 12 weeks. The trial was designed as a “discontinuation” trial, in which those who had partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed from the trial. This novel type of clinical trial design more quickly evaluates the disease-stabilizing activity of growth-inhibitory agents like cabozantinib, compared to the traditional model of randomizing all patients to either the experimental arm or placebo.

Among 398 patients evaluable with all types of cancer included in the trial, the collective overall response rate was 9 percent (34 of 398). The highest disease control rates (partial response and stable disease) at week 12 were 76 percent for liver cancer (22 of 29 patients), 71 percent for prostate cancer (71 of 100 patients), and 58 percent for ovarian cancer (32 of 51 patients). [emphasis added].

Of the 51 evaluable ovarian cancer patients noted above, 28 are platinum drug resistant, 17 are platinum drug sensitive, and 6 have unknown status. The median number of systemic treatments prior to trial enrollment was 2. The overall response rate (complete response and partial response based on modified RECIST criteria) for ovarian cancer was 12/51 (24%).  Upon breakdown, the response rate was 5/28 (18%) for platinum drug resistant patients, and 5/17 (29%) for platinum drug sensitive patients. Five additional partial responses await confirmation. After a median follow-up of 4 months (range: 1 to 11 months), the median duration of response and median progression free survival have not been reached. The most common related adverse events ( ≥grade 3) among ovarian cancer patients were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Drug dose reductions and permanent discontinuations for adverse events occurred in 43% and 10% of the ovarian cancer patients, respectively. Based on these findings, the investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. [emphasis added] Accordingly, randomization in the ovarian cancer cohort was halted & patients unblinded due to the observed high efficacy.

Fifty-nine of 68 patients with bone metastases (including patients with breast and prostate cancers and melanoma) experienced either partial or complete disappearance of the cancer on bone scans, often with significant pain relief and other improved cancer-related symptoms.

The reduction of bone metastases and pain relief was an unexpected finding in this study, Dr. Gordon said. Independent review by radiologists confirmed that bone metastases disappeared in the majority of patients who had bone metastases when they entered the study. The majority of these patients had castration-resistant prostate cancer (CRPC), but patients with breast cancer and melanoma also had disappearance of bone metastases. Bone metastases greatly contribute to morbidity and mortality in patients with these types of cancer, which typically spread to the bone.

Due to these results, the study has been expanded to include more CRPC patients. Similarly, the high rate of lasting responses in ovarian cancer patients led researchers to also expand the study to evaluate the drug’s effect on patients with a particularly resistant form of the disease known as platinum drug resistant/refractory ovarian cancer. [emphasis added]

This study expansion results will help determine the design of future phase III trials, which will assess whether the drug extends patients lives or has other longer-term benefits among patients with specific cancer types. At present, cabozantinib is being investigated for use as a single agent. Additional studies will evaluate the efficacy and tolerability of appropriate combinations with other agents for future indications.

For the solid tumor patients collectively, the most common grade three or above adverse events were fatigue (9 percent) and hand-foot syndrome (8 percent). Dose reductions were required in 41 percent of patients due to side effects; 12 percent were removed from the trial for adverse events.

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New Assay Test Predicts That 50% of Ovarian Cancers Will Respond To In Vitro PARP Inhibition

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U.K. researchers develop a new test that could be used to select ovarian cancer patients who will benefit from a new class of drugs called “PARP inhibitors.”

U.K. researchers have developed a new test that could be used to select which patients with ovarian cancer will benefit from a new class of drugs called “PARP (poly (ADP-ribose) polymerase) inhibitors,” according to preclinical research presented at the National Cancer Research Institute (NCRI) Cancer Conference held in Liverpool on November 8th.  According to the test results, approximately 50 percent of all patients with ovarian cancer may benefit from PARP inhibitors.

Dr. Asima Mukhopadhyay Discusses Her Research Into A More Tailored Treatment For Ovarian Cancer

PARP Inhibition & BRCA Gene Mutations: Exploiting Ovarian Cancer’s Inherent Defects

  • Genetics 101

DNA (deoxyribonucleic acid) is the genetic material that contains the instructions used in the development and functioning of our cells. DNA is generally stored in the nucleus of our cells. The primary purpose of DNA molecules is the long-term storage of information. Often compared to a recipe or a code, DNA is a set of blueprints that contains the instructions our cells require to construct other cell components, such as proteins and RNA (ribonucleic acid) molecules. The DNA segments that carry this genetic information are called “genes.”

A gene is essentially a sentence made up of the bases A (adenine), T (thymine), G (guanine), and C (cytosine) that describes how to make a protein. Any change in the sequence of bases — and therefore in the protein instructions — is a mutation. Just like changing a letter in a sentence can change the sentence’s meaning, a mutation can change the instruction contained in the gene. Any changes to those instructions can alter the gene’s meaning and change the protein that is made, or how or when a cell makes that protein.

Gene mutations can (i) result in a protein that cannot carry out its normal function in the cell, (ii) prevent the protein from being made at all, or (iii) cause too much or too little of a normal protein to be made.

  • Targeting DNA Repair Through PARP Inhibition

Targeting DNA repair through PARP inhibition in BRCA gene-mutated cancer cells. "DSB" stands for DNA "Double Stand Break." (Photo Credit: AstraZeneca Oncology)

Normally functioning BRCA1 and BRCA2 genes are necessary for DNA repair through a process known as “homologous recombination” (HR).  HR is a form of genetic recombination in which two similar DNA strands exchange genetic material. This process is critical to a cell’s ability to repair its DNA in the event that it becomes damaged, so the cell can continue to function.

A cell’s DNA structure can be damaged by a wide variety of intentional (i.e., select cancer treatments) or unintentional (ultraviolet light, ionizing radiation, man-made chemicals, etc.) factors.  For example, chemotherapy regimens used in the treatment of cancer, including alkylating agents, topoisomerase inhibitors, and platinum drugs, are designed to damage DNA and prevent cancer cells from reproducing.

In approximately 10 percent of inherited ovarian cancers, the BRCA 1 or BRCA2 gene is damaged or mutated.  When the BRCA1 or BRCA2 gene is mutated, a backup type of DNA repair mechanism called “base-excision repair” usually compensates for the lack of DNA repair by HR.  Base-excision repair represents a DNA “emergency repair kit.” DNA repair enzymes such as PARP, whose activity and expression are upregulated in tumor cells, are believed to dampen the intended effect of chemotherapy and generate drug resistance.

When the PARP1 protein – which is necessary for base-excision repair – is inhibited in ovarian cancer cells possessing a BRCA gene mutation, DNA repair is drastically reduced, and the cancer cell dies through so-called “synthetic lethality.”  In sum, PARP inhibitors enhance the potential of chemotherapy (and radiation therapy) to induce cell death.  Healthy cells are unaffected if PARP is blocked because they either contain one or two working BRCA1 or BRCA2 genes which do an effective DNA repair job through use of HR.

  • PARP Inhibitors: A New Class of Targeted Therapy

PARP inhibitors represent a new, targeted approach to treating certain types of cancers. PARP inhibition has the potential to overwhelm cancer cells with lethal DNA damage by exploiting impaired DNA repair function inherent in some cancers, including breast and ovarian cancers with defects in the BRCA1 gene or BRCA 2 gene, and other DNA repair molecules. Inhibition of PARP leads to the cell’s failure to repair single strand DNA breaks, which, in turn, causes double strand DNA breaks. These effects are particularly detrimental to cancer cells that are deficient in repairing double strand DNA breaks and ultimately lead to cancer cell death.

PARP inhibitors are the first targeted treatment to be developed for women with inherited forms of breast and ovarian cancer carrying faults or mutations in a BRCA gene. Early results from clinical trials are showing promise for patients with the rare inherited forms of these cancers.

Study Hypothesis: PARP Inhibitors May Be Effective Against a Large Proportion of Non-Inherited Ovarian Cancers

As noted above, PARP inhibitors selectively target HR–defective cells and have shown good clinical activity in hereditary breast and ovarian cancers associated with BRCA1 or BRCA2 mutations. The U.K. researchers hypothesized that a high proportion (up to 50%) of sporadic (non-inherited) epithelial ovarian cancers could be deficient in HR due to genetic or epigenetic inactivation of the BRCA1, BRCA2, or other HR-related genes, which occur during a woman’s lifetime. Therefore, PARP inhibitors could prove beneficial to a larger group of ovarian cancer patients, assuming a patient’s HR status can be properly identified.

To test this hypothesis, the U.K. researchers developed a functional assay to test the HR status of primary ovarian cancer cultures derived from patients’ ascitic fluid. The test, referred to as the “RAD51 assay,” scans the cancer cells and identifies which tumor samples contain defective DNA repair ability (i.e., HR-deficient) which can be targeted by the PARP inhibitor. The researchers tested the HR status of each culture, and then subjected each one to in vitro cytotoxicity testing using the potent PARP inhibitor PF-01367338 (formerly known as AG-14699).

Study Results: 90% of HR-Deficient Ovarian Cancer Cultures Respond to PARP Inhibition

Upon testing completion, the U.K. researchers discovered that out of 50 primary cultures evaluated for HR status and cytotoxicity to the PARP inhibitor, approximately 40% of the cultures evidenced normal HR activity, while 60 percent of the cultures evidenced deficient HR activity. Cytotoxicity to PARP inhibitors was observed in approximately 90 percent of the HR deficient cultures, while no cytotoxicity was seen in the cultures that evidenced normal HR activity. Specifically, the PARP inhibitor PF-01367338 was found to selectively block the spread of ovarian tumor cells with low RAD51 expression.

Conclusion

Based upon the findings above, the U.K. researchers concluded that HR-deficient status can be determined in primary ovarian cancer, and that such status correlates with in vitro response to PARP inhibition.  Accordingly, the researchers concluded that potentially 50 to 60 percent of ovarian cancers could benefit from PARP inhibitors, but they note that use of the RAD51 assay as a biomarker requires additional clinical trial testing.  Although the RAD51 assay test that was used by the U.K. researchers to examine tumor samples in the laboratory is not yet suitable for routine clinical practice, the U.K. research team hopes to refine it for use in patients.

Upon presentation of the testing results, Dr. Asima Mukhopadhyay said:

“Our results show that this new test is almost 100 percent effective in identifying which ovarian cancer patients could benefit from these promising new drugs.  We have only been able to carry out this work because of the great team we have here which includes both doctors and scientists.”

The team based at Queen Elizabeth Hospital, Gateshead and the Newcastle Cancer Centre at the NICR, Newcastle University collaborated with Pfizer to develop the new assay to test tumor samples taken from ovarian cancer patients when they had surgery.

Dr. Mukhopadhyay added:

“Now we hope to hone the test to be used directly with patients and then carry out clinical trials. If the trials are successful we hope it will help doctors treat patients in a personalised and targeted way based on their individual tumour. It is also now hoped that PARP inhibitors will be useful for a broad range of cancers and we hope this test can be extended to other cancer types.”

Dr. Lesley Walker, Cancer Research UK’s director of cancer information, said:

“It’s exciting to see the development of promising new ‘smart’ drugs such as PARP inhibitors. But equally important is the need to identify exactly which sub-groups of patients will benefit from these new treatments. Tests like this will become invaluable in helping doctors get the most effective treatments quickly to patients, sparing them from unnecessary treatments and side effects.”

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About The Researchers

Dr. Asima Mukhopadhyay is a doctor and clinical research fellow working at the Queen Elizabeth Hospital, Gateshead and the Northern Institute for Cancer Research at Newcastle University. Queen Elizabeth Hospital is run by Gateshead Health NHS Foundation Trust and is the home for gynecological oncology for the North East of England and Cumbria. She received a bursary to attend the conference, which was awarded on the merit of her work.

Key researchers on the study included Dr. Richard Edmondson, who was funded by the NHS, and Professor Nicola Curtin, who was funded by the Higher Education Funding Council. Dr Asima Mukhopadhyay is funded by the NHS.

Dr Richard Edmondson is a consultant gynecological oncologist at the Northern Gynaecological Oncology Centre, Gateshead and a Senior Lecturer at the Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, and is a member of the research team.

Nicola Curtin is Professor of Experimental Cancer Therapeutics at Newcastle University and is the principal investigator of this project.

Current and future work involves working closely with Pfizer. Pfizer developed one of the PARP inhibitors and supported this project.

About The Newcastle Cancer Centre

The Newcastle Cancer Centre at the Northern Institute for Cancer Research is jointly funded by three charities: Cancer Research UK, Leukaemia and Lymphoma Research, and the North of England Children’s Cancer Research Fund.  Launched in July 2009, the Centre is based at the Northern Institute for Cancer Research at Newcastle University.  The Centre brings together some of the world’s leading figures in cancer research and drug development. They play a crucial role in delivering the new generation of cancer treatments for children and adults by identifying new drug targets, developing new drugs and verifying the effectiveness and safety of new treatments. This collaborative approach makes it easier for researchers to work alongside doctors treating patients, allowing promising new treatments to reach patients quickly.

About the NCRI Cancer Conference

The National Cancer Research Institute (NCRI) Cancer Conference is the UK’s major forum for showcasing the best British and international cancer research. The Conference offers unique opportunities for networking and sharing knowledge by bringing together world leading experts from all cancer research disciplines. The sixth annual NCRI Cancer Conference was held from November 7-10, 2010 at the BT Convention Centre in Liverpool. For more information visit www.ncri.org.uk/ncriconference.

About the NCRI

The National Cancer Research Institute (NCRI) was established in April 2001. It is a UK-wide partnership between the government, charity and industry which promotes cooperation in cancer research among the 21 member organizations for the benefit of patients, the public and the scientific community. For more information visit www.ncri.org.uk.

NCRI members include: the Association of the British Pharmaceutical Industry (ABPI); Association for International Cancer Research; Biotechnology and Biological Sciences Research Council; Breakthrough Breast Cancer; Breast Cancer Campaign; CancerResearch UK; CHILDREN with LEUKAEMIA, Department of Health; Economic and Social Research Council; Leukaemia & Lymphoma Research; Ludwig Institute for Cancer Research; Macmillan Cancer Support; Marie Curie Cancer Care; Medical Research Council; Northern Ireland Health and Social Care (Research & Development Office); Roy Castle Lung Cancer Foundation; Scottish Government Health Directorates (Chief Scientist Office);Tenovus; Welsh Assembly Government (Wales Office of Research and Development for Health & Social Care); The Wellcome Trust; and Yorkshire Cancer Research.

Princeton Scientists Find Way To Catalog All That Goes Wrong In A Cancer Cell

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A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

Saeed Tavazoie is a professor in the Princeton University Department of Molecular Biology & the Lewis-Sigler Institute for Integrative Genomics

“For a very long time, cancer therapies have been developed by trial and error to essentially kill a broad variety of rapidly dividing cells, good and bad — that’s why they have massive side effects,” said Saeed Tavazoie, a professor in the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics, who led the research. “The goal of cancer biology is to come up with therapies that are much more rational in terms of attacking the pathways that have been co-opted by cancer cells. The big challenge is to discover these pathways so that we can restore them to their normal state.”

Writing in the Dec. 11 issue of Molecular Cell, Tavazoie, along with his colleagues Hani Goodarzi, a graduate student in molecular biology, and Olivier Elemento, a former postdoctoral researcher in the department, found they were able to systematically categorize and pinpoint the alterations in cancer pathways and to reveal the underlying regulatory code in DNA. Elemento is now on the faculty of Weill Cornell Medical College in New York.

“We are discovering that there are many components inside the cell that can get mutated and give rise to cancer,” Tavazoie said. “Future cancer therapies have to take into account these specific pathways that have been mutated in individual cancers and treat patients specifically for that.”

The researchers developed an algorithm, a problem-solving computer program that sorts through the behavior of each of 20,000 genes operating in a tumor cell. When genes are turned “on,” they activate or “express” proteins that serve as signals, creating different pathways of action. Cancer cells often act in aberrant ways, and the algorithm can detect these subtle changes and track all of them.

“At the present moment, we lump a lot of cancers together and use the same therapy,” Tavazoie said. “In the future, we are aiming to be much more precise about treating the exact processes that were perturbed by the mutations.”

Pathologists presently examining the tumors of sick patients analyze a small set of tumor characteristics in order to determine the diagnostic and prognostic class to which the cells belong. This new method could give practitioners an encyclopedic accounting of the alterations in problem cells, spelling out the nature of the disease in much greater detail.

The algorithm devised by the group scans the DNA sequence of a given cell — its genome — and deciphers which sequences are controlling what pathways and whether any are acting differently from the norm. By deciphering the patterns, the scientists can conjure up the genetic regulatory code that is underlying a particular cancer.

The scientists developed the technique by employing modern methods of systems biology, where researchers seek to understand how components of living systems like cells work together to orchestrate processes, using powerful computers to sort vast arrays of data.

“Part of the promise of genomics and systems biology is the discovery of specific pathways of disease and finding ways to target them precisely,” Tavazoie said. “We have focused on revealing what these pathways are.”

The challenge for others, he said, will be to design specific therapies for such diseases, a process that could take many years. “This is an important first step,” Tavazoie added.

The method ultimately could work for any type of cancer and paves the way for rational approaches to treating a host of other diseases from diabetes to neurological disorders, the scientists said.

The research was funded by the National Human Genome Research Institute of the National Institutes of Health.

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President of M.D. Anderson Outlines 10 Steps To Achieve Progress Against Cancer.

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“The Houston Chronicle recently published a commentary by John Mendelsohn, M.D., president of M. D. Anderson, outlining actions the nation should take to achieve great progress against cancer. … Here are 10 steps we can take to ensure that deaths decrease more rapidly, the ranks of survivors swell, and an even greater number of cancers are prevented in the first place. …”

“Ten Pieces Help Solve Cancer Puzzle

John Mendelsohn, M.D., President, The University of Texas M.D. Anderson Cancer Center

John Mendelsohn, M.D., President, The University of Texas M.D. Anderson Cancer Center

The Houston Chronicle recently published a commentary by John Mendelsohn, M.D., president of M. D. Anderson, outlining actions the nation should take to achieve great progress against cancer.

An American diagnosed with cancer today is very likely to join the growing ranks of survivors, who are estimated to total 12 million and will reach 18 million by 2020. The five-year survival rate for all forms of cancer combined has risen to 66%, more than double what it was 50 years ago.

Along with the improving five-year survival rates, the cancer death rate has been falling by 1% to 2% annually since 1990.

According to the World Health Organization, cancer will be the leading worldwide cause of death in 2010. Over 40% of Americans will develop cancer during their lifetime.

While survival rates improve and death rates fall, cancer still accounts for one in every five deaths in the U.S., and cost this nation $89.0 billion in direct medical costs and another $18.2 billion in lost productivity during the illness in 2007, according to the National Institutes of Health.

Here are 10 steps we can take to ensure that deaths decrease more rapidly, the ranks of survivors swell, and an even greater number of cancers are prevented in the first place.

#1.  Therapeutic cancer research should focus on human genetics and the regulation of gene expression.

Cancer is a disease of cells that have either inherited or acquired abnormalities in the activities of critical genes and the proteins for which they code. Most cancers involve several abnormally functioning genes – not just one – which makes understanding and treating cancer terribly complex. The good news is that screening for genes and their products can be done with new techniques that accomplish in days what once took years.

Knowledge of the human genome and mechanisms regulating gene expression, advances in technology, experience from clinical trials, and a greater understanding of the impact of environmental factors have led to exciting new research approaches to cancer treatment, all of which are being pursued at M. D. Anderson:

  • Targeted therapies.  These therapies are designed to counteract the growth and survival of cancer cells by modifying, replacing or correcting abnormally functioning genes or their RNA and protein products, and by attacking abnormal biochemical pathways within these cells.
  • Molecular markers.  Identifying the presence of particular abnormal genes and proteins in a patient’s cancer cells, or in the blood, will enable physicians to select the treatments most likely to be effective for that individual patient.
  • Molecular imaging.  New diagnostic imaging technologies that detect genetic and molecular abnormalities in cancers in individual patients can help select optimal therapy and determine the effectiveness of treatment within hours.
  • Angiogenesis.  Anti-angiogenesis agents and inhibitors of other normal tissues that surround cancers can starve the cancer cells of their blood supply and deprive them of essential growth-promoting factors which must come from the tumor’s environment.
  • Immunotherapy. Discovering ways to elicit or boost immune responses in cancer patients may target destruction of cancer cells and lead to the development of cancer vaccines.

#2.  Better tests to predict cancer risk and enable earlier detection must be developed.

New predictive tests, based on abnormalities in blood, other body fluids or tissue samples, will be able to detect abnormalities in the structure or expression of cancer-related genes and proteins. Such tests may predict the risk of cancer in individuals and could detect early cancer years before any symptoms are present.

The prostate-specific antigen test for prostate cancer currently is the best known marker test to detect the possible presence of early cancer before it has spread. Abnormalities in the BRCA 1 and BRCA 2 genes predict a high risk for breast cancer, which can guide the decisions of physicians and patients on preventive measures. Many more gene-based predictors are needed to further our progress in risk assessment and early detection.

#3.  More cancers can and must be prevented.

In an ideal world, cancer “care” would begin with risk assessment and counseling of a person when no malignant disease is present. Risk factors include both inherited or acquired genetic abnormalities and those related to lifestyle and the environment.

The largest risk factor for cancer is tobacco smoking, which accounts for nearly one-third of all cancer deaths. Tobacco use should be discouraged with cost disincentives, and medical management of discontinuing tobacco use must be reimbursed by government and private sector payors.

Cancer risk assessment should be followed by appropriate interventions (either behavioral or medical) at a pre-malignant stage, before a cancer develops. Diagnosis and treatment of a confirmed cancer would occur only when these preventive measures fail.

A full understanding of cancer requires research to identify more completely the genetic, environmental, lifestyle and social factors that contribute to the varying types and rates of cancer in different groups in this country and around the world. A common cancer in Japan or India, for example, often is not a common cancer in the U.S. When prostate cancer occurs in African-Americans it is more severe than in Caucasians. A better understanding of the factors that influence differences in cancer incidence and deaths will provide important clues to preventing cancer in diverse populations worldwide.

#4.  The needs of cancer survivors must become a priority.

Surviving cancer means many things: reducing pain, disability and stress related to the cancer or the side effects of therapy; helping patients and their loved ones lead a full life from diagnosis forward; preventing a second primary cancer or recurrence of the original cancer; treating a difficult cancer optimally to ensure achieving the most healthy years possible, and more.  Since many more patients are surviving their cancers – or living much longer with cancer – helping them manage all the consequences of their disease and its treatment is critically important.  It is an area ripe for innovative research and for improvement in delivery of care.

#5.  We must train future researchers and providers of cancer care.

Shortages are predicted in the supply of physicians, nurses and technically trained support staff needed to provide expert care for patients with cancer.  On top of this, patient numbers are projected to increase.  We are heading toward a “perfect storm” unless we ramp up our training programs for cancer professionals at all levels.   The pipeline for academic researchers in cancer also is threatened due to the increasing difficulty in obtaining peer-reviewed research funding. We must designate more funding from the NIH and other sources specifically for promising young investigators, to enable them to initiate their careers.

#6.  Federal funding for research should be increased.

After growing by nearly 100% from 1998-2002, the National Cancer Institute budget has been in decline for the past four years. Through budget cuts and the effects of inflation, the NCI budget has lost approximately 12% of its purchasing power.  Important programs in tobacco control, cancer survivorship and support for interdisciplinary research have had significant cuts.  The average age at which a biomedical researcher receives his or her first R01 grant (the gold standard) now stands at 42, hardly an inducement to pursue this field. This shrinks the pipeline of talented young Americans who are interested in careers in science, but can find easier paths to more promising careers elsewhere.  Lack of adequate funding also discourages seasoned scientists with outstanding track records of contributions from undertaking innovative, but risky research projects.  The U.S. leadership in biomedical research could be lost.

Biomedical research in academic institutions needs steady funding that at least keeps up with inflation and enables continued growth.

#7.  The pace of clinical research must accelerate.

As research ideas move from the laboratory to patients, they must be assessed in clinical trials to test their safety and efficacy. Clinical trials are complicated, lengthy and expensive, and they often require large numbers of patients.  Further steps must be taken to ensure that efficient and cost-effective clinical trials are designed to measure, in addition to outcomes, the effects of new agents on the intended molecular targets. Innovative therapies should move forward more rapidly from the laboratory into clinical trials.

The public needs to be better educated about clinical trials, which in many cases may provide them with access to the best care available.  Greater participation in trials will speed up drug development, in addition to providing patients with the best options if standard treatments fail.  The potential risks and benefits of clinical trials must continue to be fully disclosed to the patients involved, and the trials must continue to be carefully monitored.

The issue of how to pay for clinical trials must be addressed. The non-experimental portion of the costs of care in clinical trials currently are borne in part by Medicare, and should be covered fully by all payors. The experimental portion of costs of care should be covered by the owner of the new drug, who stands to benefit from a new indication for therapeutic use.

#8.  New partnerships will encourage drug and device development.

One way to shorten the time for drug and device development is to encourage and reward collaboration among research institutions, and collaboration between academia and industry.  Increasingly, partnerships are required to bring together sufficient expertise and resources needed to confront the complex challenges of treating cancer. There is enormous opportunity here, but many challenges, as well.

Academic institutions already do collaborate, but we need new ways to stimulate increased participation in cooperative enterprises.

Traditionally, academic institutions have worked with biotech and pharmaceutical companies by conducting sponsored research and participating in clinical trials.  By forming more collaborative alliances during the preclinical and translational phases prior to entering the clinic, industry and academia can build on each other’s strengths to safely speed drug development to the bedside. The challenge is that this must be done with agreements that involve sharing, but also protect the property rights and independence of both parties.

The results of all clinical trials must be reported completely and accurately, without any influence from conflicts of interest and with full disclosure of potential conflicts of interest.

#9. We must provide access to cancer care for everyone who lives in the U.S.

More than 47 million Americans are uninsured, and many others are underinsured for major illnesses like cancer. Others are uninsurable because of a prior illness such as cancer.  And many are indigent, so that payment for care is totally impossible.

Depending on where they live and what they can afford, Americans have unequal access to quality cancer care. Treatment options vary significantly nationwide. We must find better ways to disseminate the best standards of high-quality care from leading medical centers to widespread community practice throughout the country.

Cancer incidence and deaths vary tremendously among ethnic and economic groups in this country. We need to address the causes of disparities in health outcomes and move to eliminate them.

We are unique among Western countries in not providing direct access to medical care for all who live here. There is consensus today among most Americans and both political parties that this is unacceptable.  Especially for catastrophic illnesses like cancer, we must create an insurance system that guarantees access to care.

A number of proposals involving income tax rebates, vouchers, insurance mandates and expanded government insurance programs address this issue. Whatever system is selected should ensure access and include mechanisms for caring for underserved Americans.  The solution will require give-and-take among major stakeholders, many of which benefit from the status quo.  However, the social and economic costs have risen to the point that we have no choice.

#10.  Greater attention must be paid to enhancing the quality of cancer care and reducing costs.

New therapies and medical instruments are expensive to develop and are a major contributor to the rising cost of medical care in the U.S.  The current payment system rewards procedures, tests and treatments rather than outcomes.  At the same time, cancer prevention measures and services are not widely covered.  A new system of payment must be designed to reward outcomes, as well as the use of prevention services.

Quality of care can be improved and costs can be reduced by increasing our efforts to reduce medical errors and to prescribe diagnostic tests and treatments only on the basis of objective evidence of efficacy.

A standardized electronic medical record, accessible nationwide, is essential to ensuring quality care for patients who see multiple providers at multiple sites, and we are far behind many other nations.  Beyond that, a national electronic medical record could provide enormous opportunities for reducing overhead costs, identifying factors contributing to many illnesses (including cancer), determining optimal treatment and detecting uncommon side effects of treatment.

What the future holds in store.

I am optimistic. I see a future in which more cancers are prevented, more are cured and, when not curable, more are managed as effectively as other chronic, life-long diseases. I see a future in which deaths due to cancer continue to decrease.

Achieving that vision will require greater collaboration among academic institutions, government, industry and the public.  Barriers to quality care must be removed.  Tobacco use must be eradicated.  Research must have increased funding.  Mindful that our priority focus is on the patient, we must continue to speed the pace of bringing scientific breakthroughs from the laboratory to the bedside.

M. D. Anderson resources:

John Mendelsohn, M.D.”

Primary Source:  Ten Pieces Help Solve Cancer Puzzle, by John Mendelsohn, M.D., Feature Article, The University of Texas M.D. Anderson Cancer Center Cancer News, Mar. 2009.

Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors

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“The Massachusetts General Hospital Cancer Center has recently opened a new Translational Research Laboratory that will uncover the genetic codes and gene mutations from almost all of its cancer patients. … By embarking on such an ambitious approach, Cancer Center pathologists and oncologists hope to gather specific information about tumor properties that will lead to targeted therapies and better personalized treatments. Mass General will be the first and only cancer center to conduct molecular profiling of positive biopsies and tumors from all patients as part of basic patient care. …”

“Genetic profiling

09/Mar/2009

massgenlab

Massachusetts General Hospital Cancer Center Opens Molecular Pathology Lab to Genetically Profile All Patient Tumors

The Massachusetts General Hospital Cancer Center has recently opened a new Translational Research Laboratory that will uncover the genetic codes and gene mutations from almost all of its cancer patients. Previously only a sampling of patients had their tumors analyzed in such a comprehensive fashion.

By embarking on such an ambitious approach, Cancer Center pathologists and oncologists hope to gather specific information about tumor properties that will lead to targeted therapies and better personalized treatments. Mass General will be the first and only cancer center to conduct molecular profiling of positive biopsies and tumors from all patients as part of basic patient care.

Scientists and researchers have already identified over 110 genetic mutations responsible for causing tumor growth, many of which are involved in several different types of cancers. Codirectors of the Transplational Research Laboratory, Leif Ellisen, MD, PhD, and A. John Iafrate, MD, PhD, have equipped the lab with state-of-the-art robotic technology, which will make it possible to quickly genotype tumor specimens within a short period of time.

‘This new and improved classification of cancers that we are doing is intended to give our oncologists more information about a individual patient’s cancer, so they can treat it in a very specific way, thereby significantly increasing the odds of success,’ says Iafrate.

Several new cancer drugs that are currently available or in development are able to block some of the mutations and pathways that cause tumor cells to proliferate. By targeting tumor gene mutations with these smart drugs, doctors may be able to eradicate malignant cells without using traditional treatments like chemotherapy and radiation, which have significant side effects.

The lab’s new tumor genotyping initiative should also expedite the time it takes to find the right drug for the right patient. According to Ellisen, ‘If we are able to identify a mutation in, say, a case of lung cancer, and we know that a particular drug has been successful in treating colon cancer patients with the same mutation, then we have good reason to believe that drug will work turning off the cancer-causing mutation in the lung cancer patient as well.’

The lab will start with the genotyping of Mass General’s lung cancer patients and phase in different disease groups over the next few weeks. It is anticipated that the profiling of all possible patient tumors will occur gradually over the coming months.

Learn more about research at the Cancer Center ”

Cited Source:  Massachusetts General Hospital Cancer Center opens molecular pathology lab to genetically profile all patient tumors, News, Massachusetts General Hospital, Mar. 9, 2009.

Update:

  • Making Personalized Cancer Care Routine, In Depth, NCI Cancer Bulletin, Volume 6 / Number 11, National Cancer Institute, June 2, 2009 (noting that Massachusetts General Hospital & Memorial Sloan-Kettering Cancer Center are performing genetic profiling of all lung cancer tumors).