Archive for the ‘Melanoma’ Category

Melanoma: Whole-genome sequencing of 25 tumors confirms role of sun damage, reveals new genetic alterations

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Posted 10 May 2012 — by James Street
Category Gene sequencing, genetic research, Melanoma, Melanoma

May 9, 2012 by Elizabeth Cooney in Cancer

Melanoma – the deadliest and most aggressive form of skin cancer – has long been linked to time spent in the sun. Now a team led by scientists from the Broad Institute and Dana-Farber Cancer Institute has sequenced the whole genomes of 25 metastatic melanoma tumors, confirming the role of chronic sun exposure and revealing new genetic changes important in tumor formation.

In an article published online May 9 in Nature, the authors provide the first high-resolution view of the genomic landscape of human tumors. Previous genetic analyses have focused on the exomes of many types of cancer tumors, concentrating on the tiny fraction of the genome that provides the genetic code for producing proteins. Whole genomes contain a wealth of genetic information, and by sequencing and analyzing 25 metastatic melanoma tumors – a significant technical and computational feat – scientists can learn vastly more about the variety of genetic alterations that matter in melanoma.

“Sequencing the whole genome certainly adds a richness of discovery that can’t be fully captured with a whole exome,” said Levi A. Garraway, a senior associate member of the Broad Institute, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, and co-senior author of the paper.

“By looking across the entire genome you can more accurately determine the background mutation rate and the different classes of mutations, and more confidently describe the pattern of ultraviolet-induced mutagenesis in melanoma,” said Michael F. Berger, co-first author of the paper. He worked in the Broad’s cancer genome analysis group and with Garraway as a research scientist and computational biologist before moving to Memorial Sloan-Kettering Cancer Center.

When the scientists explored the whole genome data generated and analyzed at the Broad, they found that the rates of genetic mutations rose along with chronic sun exposure in patients, confirming the role of sun damage in disease development.

“Whole-genome analysis of human melanoma tumors shows for the first time the existence of many structural rearrangements in this tumor type,” said Lynda Chin, a senior associate member of the Broad and co-senior author of the paper. Formerly at Dana-Farber and Harvard Medical School, she is now chair of the Department of Genomic Medicine at the University of Texas MD Anderson Cancer Center.

As expected, the scientists detected known BRAF and NRAS mutations in 24 of the 25 tumors. Both genes are involved in sending signals important in cell growth.

One other gene leaped out: PREX2, previously implicated in breast cancer for blocking a tumor-suppressor pathway, was altered in 44 percent of patients. In a larger validation cohort of 107 tumors, the frequency of the mutation was 14 percent.

PREX2 is mutated in a convergence of genetic disruption that appears to accelerate tumor development. Its mutations occurred not just at hot spots that typically turn on an oncogene, a type of cancer-causing gene, and drive cancer forward. The alterations were also scattered across the length of the gene in a pattern typically seen when another type of cancer-causing gene, known as tumor suppressors, are turned off.

“The pattern of mutations here looks a lot more like a tumor suppressor gene, but from the functional experiments, it behaved more like an oncogene,” Berger said.

When PREX2 functions normally, it interacts with the protein PTEN. PTEN is well known as a tumor suppressor, controlling growth in normal cells. Mouse experiments in Chin’s lab at Dana-Farber showed that PREX2 mutations spurred tumor growth in ways that are not fully understood.

“We still can’t say we know exactly how it works,” Garraway said. “PREX2 may be in a very interesting new category of mutated cancer genes that point us to at least one and maybe more pathways that would be worth targeting therapeutically in melanoma.”

The identification of PREX2 may be the tip of the iceberg.

“New melanoma genes remain to be discovered by this unbiased approach, as illustrated by the discovery of PREX2 and the demonstration of its oncogenicity in vivo,” said Chin.

More information: Berger, Hodis, Heffernan, Deribe, Lawrence et al. “Melanoma genome sequencing reveals frequent PREX2 mutations.” Nature, May 10, 2012. doi:10.1038/nature11071

Provided by Massachusetts Institute of Technology (news : web)

Bright future ahead for antibody cancer therapy

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Posted 18 Mar 2012 — by James Street
Category CTLA-4, Immune System, ipilimumab, Melanoma, Melanoma, Monoclonal Antibody

WASHINGTON –Antibodies, once touted as the “magic bullets” of cancer care, are now fulfilling that promise and more advances are on the way, say cancer researchers at the Georgetown Lombardi Comprehensive Cancer Center

In a review article posted online March 16 in Cell, the researchers say that refinements and modifications of monoclonal antibody drugs — several of which have already revolutionized the care of breast and colon cancer –are now being tested in most tumor types.

These modifications allow antibody drugs to bind to more than one target on a cell, and to directly stimulate the body’s immune response to promote vaccine-like antitumor effects. Others have been designed to boost their killing power by carrying a payload of radiation, toxins, or other chemicals.

‘We are heading into an era where antibodies will not just be components of an effective therapeutic strategy, they will be at the core of an oncologist’s treatment plan for patients,” says the review’s lead author, Louis M. Weiner, M.D., director of Georgetown Lombardi Comprehensive Cancer Center, an internationally recognized expert in immunotherapy research.

“Advancement in antibody cancer treatment is not a minor advance or a trivial victory. This is big time stuff,” Weiner said in an interview.

His co-authors on the review are Joseph Murray and Casey W. Shuptrine, both graduate students in the Tumor Biology Training Program at Georgetown Lombardi.

A good example of the new class of antibody-based therapies is ipilimumab, a drug approved in 2011 to treat patients with metastatic melanoma, says Weiner. Ipilimumab is a fully human antibody which binds to an immune antigen (CTLA-4) on cancer cells that transmits a signal inhibiting other immune cells from destroying the tumor. Ipilimumab blocks CTLA-4, thereby inducing an active immune response.

“This agent turns off the brakes of an immune response against melanoma, liberating the body to set up long term protectiion against the cancer,” Weiner says. “About 10 percent of patients with metastatic melanoma who use it go into long-term remission, and may well be cured.”

Antigens are substances, often a cell surface receptor, which causes the immune system to produce an antibody against it, as a way to target and kill the cell. Therefore, antibody agents targeted to a receptor on a cancer cell have the unique capacity to target and kill cancer cells while activating an immune response. A monoclonal antibody (mAb) is an artificially produced antibody designed to bind to a specific cancer antigen, and currently 11 mAbs are approved for use in oncology, Most of these were approved in the last decade. The most commonly used are trastuzumab (Herceptin) to treat HER2-positive breast cancer and rituximab (Rituxan) for specific forms of lymphoma and leukemia.

Advanced antibody engineering techniques are being used to create more effective treatments, Weiner says. One group, known as bispecific antibodies (bsAbs) can bind to two different tumor antigens, or to a tumor antigen and another target in the tumor microenvironment, such as an immune system killer cell. Other mAbs are being designed as “conjugates” to carry a toxic payload, which can be a radionuclide, other drugs, toxins, or enzymes. Researchers are also now increasing the capacity of antibodies to be absorbed by cancer cells so that they can bind to antigens inside the cell – not just on the outside of the cell surface.

“The field of cancer antibodies is definitely maturing. There are scores of new cancer antibody agents now being tested in virtually every kind of solid cancer, and oncologists, researchers and pharmaceutical companies are excited about their promise,” Weiner says. “To me this is like watching a child grow up and do well — very well — in young adulthood.”

###

The work was supported by funding from the National Cancer Institute. Weiner serves as an expert consultant on cancer immunotherapy to several pharmaceutical companies, none of whose products are mentioned in this article.

About Georgetown Lombardi Comprehensive Cancer Center

Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 40 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health. In fiscal year 2010-11, GUMC accounted for 85 percent of the university’s sponsored research funding.

Treatment Offers an Alternative to Amputation for Patients with Advanced Skin Cancer

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Posted 13 Dec 2011 — by James Street
Category Chemotherapy, Melanoma, Melanoma

Published Tuesday, Dec. 13, 2011


CHICAGO, Dec.13, 2011 — Northwestern Medicine surgeons now offering isolated limb infusion

CHICAGO, Dec.13, 2011 /PRNewswire-USNewswire/ — Patients diagnosed with metastatic melanoma on a limb have traditionally had limited options for fighting the often deadly form of skin cancer.  Surgery is often impossible or would require large portions of tissue be removed – even the entire arm or leg.  Northwestern Medicine® oncologists are now offering an alternative approach that focuses on saving the limb while eliminating or shrinking the cancer, and may avoid the need for radical surgery altogether.  The procedure, called isolated limb infusion, is performed at only a handful of medical centers across the country due to the complexity of the approach and expertise of the team required.

During the procedure, doctors use a tourniquet to temporarily stop blood flow to the limb. A high-dose of heated chemotherapy medication is then injected into a main artery of the affected limb using a catheter to target the cancer. By isolating the limb, doctors are able to prevent the otherwise toxic high-dose chemotherapy drugs from affecting other organs.  Following the treatment, drugs are flushed out through the main vein with a second catheter and circulation to the limb is returned to normal.

“This is a remarkable and frequently effective option for treating patients who otherwise would face amputation or disfiguring surgery,” said Karl Bilimoria, MD, surgical oncologist at Northwestern Memorial and member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Melanoma can take over a patient’s arm or leg without having spread to other places in the body.  In those cases, this treatment allows the limb to be treated and preserved.  According to Bilimoria, approximately two-thirds of patients will significantly benefit from the treatment, with noticeable shrinkage of the tumor in as little as one month.

“Isolated limb infusion is capable of providing long-term tumor control and better long-term survival,” said Bilimoria, who is also an assistant professor of surgery at Northwestern University Feinberg School of Medicine. ”We are pleased to be able to offer an alternative that can increase their chance of survival, preserve their limb, and improve their quality of life.”

For patients like Larry Black, who was diagnosed with melanoma in the fall of 2010, hearing that an alternative treatment was available provided hope at a time when he felt like he was in a losing battle with cancer.

“Before coming to Chicago, I had undergone several treatments that failed to get rid of the cancer,” said Black.  “I was watching the spots on my arm grow and was worried nothing could be done to stop it from spreading.  When I got a second opinion from Dr. Bilimoria and learned  there may be a different treatment that could help, I had a renewed sense of hope and was ready to keep fighting.”

Black was the first patient to be treated with isolated limb infusion at Northwestern Memorial.

“There has been a noticeable decrease in the number and size of the tumors on Larry’s arm and he no longer requires pain medication,” said Bilimoria.

Black is grateful he learned about this option and thankful that he did not have to turn to amputation.  “I need this arm to hold my fishing rod,” said Black.

The outpatient procedure takes approximately two hours to complete.  Side effects are limited, but the limb must be monitored closely in the hospital for a few days following surgery.

For more information about isolated limb infusion or other cancer treatments available at Northwestern Memorial and the Lurie Cancer Center, please call 312-926-0779 or visit us online.

About Northwestern Memorial HealthCareNorthwestern Memorial HealthCare is the parent corporation of Chicago’s Northwestern Memorial Hospital, an 894-bed academic medical center hospital and Northwestern Lake Forest Hospital, a 205-bed community hospital located in Lake Forest, Illinois.

About Northwestern Memorial HospitalNorthwestern Memorial is one of the country’s premier academic medical center hospitals and is the primary teaching hospital of the Northwestern University Feinberg School of Medicine.  Along with its Prentice Women’s Hospital and Stone Institute of Psychiatry, the hospital comprises 894 beds, 1,603 affiliated physicians and 7,144 employees.  Northwestern Memorial is recognized for providing exemplary patient care and state-of-the art advancements in the areas of cardiovascular care; women’s health; oncology; neurology and neurosurgery; solid organ and soft tissue transplants and orthopaedics.

Northwestern Memorial possesses nursing Magnet Status, the nation’s highest recognition for patient care and nursing excellence.  It is also listed in 13 clinical specialties in U.S. News & World Report’s 2011 “America’s Best Hospitals” guide and ranks No. 1 in Chicago in the 2011 U.S. News & World Report Best Hospitals metro area rankings. For 12 years running, Northwestern Memorial has been rated among the “100 Best Companies for Working Mothers” guide by Working Mother magazine. The hospital is a recipient of the prestigious National Quality Health Care Award and has been chosen by Chicagoans as the Consumer Choice according to the National Research Corporation’s annual survey for 11 years.

SOURCE Northwestern Memorial Hospital

Novel Cancer Treatment Combination Receives Approval to Begin First-in-Human Testing for Patients with Advanced Metastatic Melanoma

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Posted 09 Dec 2011 — by James Street
Category Galectin, GM-CT-01, Melanoma, Molecular, Vaccine

press release

Dec. 8, 2011, 12:42 p.m. EST

Trial to Evaluate the Safety and Efficacy of Immunomodulatory Compound, GM-CT-01, with Peptide Vaccine

NEWTON, Mass. & NEW YORK & BRUSSELS, Dec 08, 2011 (BUSINESS WIRE) — Galectin Therapeutics, the Cancer Centre at the Cliniques universitaires Saint-Luc and the Ludwig Institute for Cancer Research (LICR) announced today that they will initiate a Phase 1/2 safety and efficacy trial testing a novel treatment combination in patients with advanced metastatic melanoma. The Belgian Federal Agency of Medicine and Health Products (FAMHP) granted approval to evaluate Galectin Therapeutics’ carbohydrate-based galectin receptor inhibitor, GM-CT-01, together with an LICR peptide vaccine. The trial will enroll up to 46 patients from four clinical centers in Belgium and Luxembourg.

“This trial marks Galectin Therapeutics entry into the clinic with one of our lead programs and represents a substantial opportunity for us to learn about the broad immunotherapy potential for inhibiting galectin proteins which are over expressed by nearly all tumors,” commented Peter G. Traber, M.D., President, Chief Executive Officer and Chief Medical Officer, Galectin Therapeutics.

“Preclinical studies have shown that GM-CT-01 enhances the ability of tumor-infiltrating T-lymphocytes to kill cells. Therefore, it is our hope that combining GM-CT-01 with an anti-cancer vaccine will induce a more efficient immune response that will aid in the shrinkage of metastatic tumors in patients with advanced metastatic melanoma,” said Dr. Pierre van der Bruggen of LICR.

All patients will receive either MAGE-3.A1 or NA17.A2 injections at three-week intervals throughout the study and GM-CT-01 intravenously every three days, beginning after the third dose of the peptide vaccine. Patients with at least one superficial metastatic lesion will also receive GM-CT-01 at the site of the lesion.

Partial or complete response will serve as the efficacy endpoint for the trial. Patient enrollment will commence in early 2012, and initial safety data are expected by the end of 2012. The Cliniques universitaires Saint-Luc and LICR will fund the first stage of the trial, and the second stage will be funded through grants and/or Galectin Therapeutics funds.

Each of the two peptide vaccines has already been tested in advanced melanoma patients, either alone, with or without immunological adjuvant, or in other vaccine combinations. These vaccines were well tolerated and were associated with evidence of tumor regression in a minority of patients (5 to 20%). The GM-CT-01 compound has shown initial success in preclinical studies in improving the efficacy of T-lymphocytes in killing cells. GM-CT-01 has proven safe in 100 patients in previous human studies.

There are more than 100,000 individuals around the world diagnosed with melanoma each year. Current treatment options for patients with melanoma include chemotherapy, radiotherapy and immune modulating drugs, all of which have shown limited success in shrinking tumors and extending survival time in a subset of patients with advanced disease. This Phase 1/2 study will test a novel treatment concept: combining active vaccination and immunomodulatory agents to evaluate whether they are safe and have an impact in shrinking or eliminating metastatic melanoma tumors.

“We look forward to enrolling patients in this first-of-its-kind study to examine the impact of inhibiting tumor-secreted galectins for enhancing the ability of the immune system to attack cancer cells and have a therapeutic effect in patients with melanoma,” said Prof. Jean-Francois Baurain of the Cancer Centre at the Cliniques universitaires Saint-Luc, the principal investigator on the trial.

About Galectin Therapeutics

Galectin Therapeutics GALT +11.57% is developing promising carbohydrate-based therapies for fibrotic liver disease and cancer based on the Company’s unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at http://www.galectintherapeutics.com .

US approves new drug against skin cancer

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Posted 17 Aug 2011 — by James Street
Category genetic research, Melanoma, Melanoma

By Kerry Sheridan (AFP) – 14 hours ago

WASHINGTON — A breakthrough drug that could extend survival in some patients with advanced skin cancer was approved on Wednesday by US regulators, offering the first new treatment for melanoma in 13 years.

Zelboraf was given the nod by the US Food and Drug Administration more than two months early, after a global clinical trial showed it could work better than chemotherapy by targeting a gene mutation found in about half of patients.

While the drug, made by Genentech, a US subsidiary of the Swiss pharmaceutical giant Roche, is far from a cure for people with metastatic melanoma, its approval was hailed as “a really big deal” by research advocates.

Zelboraf (vemurafenib) is the second melanoma drug to obtain approval this year, following Yervoy (ipilimumab) in March.

The treatment only works in patients with advanced melanoma whose tumors express a gene mutation called BRAF V600E, meaning it could help about 10,000 patients in the United States, according to experts.

Just a few treatments for melanoma currently exist, with little success in extending the life of patients. Most people diagnosed with advanced melanoma die within 11 months, said Tim Turnham of the Melanoma Research Foundation.

“This is a really big deal,” Turnham told AFP. “This is two drugs after 13 years of nothing.”

Zelboraf works by blocking a protein that is involved with cell growth.

“This is a whole new approach to tackling melanoma,” explained Turnham. “This actually goes into the malignant tumor cells and shuts them down.”

The FDA said the approval of Zelboraf comes with a diagnostic test called the cobas 4800 BRAF V600 mutation test to determine if patients have the type of cancer that the drug can treat.

“Today’s approval of Zelboraf and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” said Alberto Gutierrez, director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health.

The regulatory agency had set a goal of deciding on the drug by late October, but issued the decision early after a promising results from an international trial of 675 patients with late-stage melanoma with the BRAF V600E mutation.

The FDA said that compared to another anti-cancer therapy, dacarbazine, Zelboraf showed longer overall survival, or the length of time between the start of treatment and the patient’s death.

When measuring median survival, those on chemotherapy reached eight months with 64 percent of patients still living, while the median point for Zelboraf “has not been reached (77 percent still living),” the FDA said.

Early findings from that phase-three clinical trial were presented in Chicago at June’s conference of the American Society of Clinical Oncology (ASCO).

Lead author Paul Chapman, a physician at Memorial Sloan-Kettering Cancer Center in New York, called Zelboraf “the first successful melanoma treatment tailored to patients who carry a specific gene mutation in their tumor.”

Side effects include joint pain, rash, hair loss, fatigue, nausea, and sensitivity to sun exposure, and those taking it should stay out of the sun, the FDA said.

Roche said the drug should be available in the United States in two weeks, and said it has submitted new drug applications for Zelboraf in the European Union, Australia, New Zealand, Brazil, India, Mexico and Canada.

However, Turnham noted that while the drug can work wonders for some patients, its effects do not typically last.

“For a lot of people, it works like magic. Two weeks after taking Zelboraf, the cancer is gone. It’s amazing the way it melts tumors away.

“But the median response time is six months, then the tumors start coming back. There is a real need to find ways to extend that response time, perhaps by combining it with other drugs,” he said.

The National Cancer Institute says 68,130 new cases of melanoma were diagnosed in the United States last year and about 8,700 people died from the disease.

According to the World Health Organization, skin cancer leads to 66,000 deaths annually worldwide, 80 percent of which involve melanomas.

More than half the patients are under age 59.

Quercetin and tamoxifen sensitize human melanoma cells to hyperthermia

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Posted 09 Jun 2011 — by James Street
Category Hyperthermia, Melanoma, quercetin

Piantelli, M.; Tatone, D.; Castrilli, G.; Savini, F.; Maggiano, N.; Larocca, L. M.; Ranelletti, F. O.; Natali, P. G.*

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Abstract

Hyperthermia produces regression of human cancer. Because hyperthermia has produced only limited results, attention has focused on searching for substances able to sensitize tumour cells to the effects of hyperthermia. The flavonoid quercetin has been reported to be a hyperthermic sensitizer in ovarian and uterine cervical tumours and in leukaemia. Quercetin and tamoxifen inhibit melanoma cell growth. We therefore investigated whether quercetin and tamoxifen can sensitize M10, M14 and MNT1 human melanoma cells to hyperthermia. We observed that both quercetin and tamoxifen synergize with hyperthermia (42.5°C) in reducing the clonogenic activity of M14 and MNT1 and in inducing apoptotic cell death in all three cell lines. As revealed by flow cytometric and Northern blot analyses, quercetin and tamoxifen reduced heat shock protein-70 expression at both protein and mRNA levels. Our results suggest that quercetin and tamoxifen can be usefully combined with hyperthermia in the therapy of recurrent and/or metastatic melanoma.

Ludwig Institute for Cancer Research and Polaris Group Form Collaboration to Expand Development of Polaris’ Novel Cancer Drug, ADI-PEG 20

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Posted 19 May 2011 — by James Street
Category Arginine Depletors, Drug Companies, Drugs, Lung Metastases, Melanoma, Metastases

NEW YORK and SAN DIEGO, May 18, 2011 /PRNewswire/ — Ludwig Institute for Cancer Research LTD (LICR) and Polaris Group (Polaris) today announced the formation of a collaboration to expand development of Polaris’ novel cancer drug, pegylated arginine deiminase (ADI-PEG 20). ADI-PEG 20 kills tumor cells by depletion of the amino acid arginine.

As part of the collaboration, LICR and Polaris will explore further the potential of ADI-PEG 20 as a cancer therapy and aim to identify other amino acid-degrading enzymes with anti-tumor activity.  The collaboration builds on an existing relationship under which LICR and Polaris have studied ADI-PEG 20 in melanoma and are currently conducting a Phase 2 clinical trial in small cell lung cancer (SCLC) that was initiated in December 2010.  LICR is the sponsor of the SCLC clinical trial, and LICR and Polaris are sharing expenses and resources to conduct this trial.

“We are delighted to have this agreement with Polaris,” said Andrew Simpson, Ph.D., Scientific Director of LICR. “This collaboration builds on the work of Lloyd Old, M.D. of LICR and his seminal work on amino acid-degrading enzymes, including asparaginase and arginine deiminase, as anti-cancer treatments. We look forward to continuing our close working relationship with Polaris.”

Bor-Wen Wu, Ph.D., Chief Executive Officer of Polaris, said, “This agreement is the fruit of many years of collaboration between LICR and Polaris, and is an opportunity to leverage the strengths of both organizations to attempt to bring ADI-PEG 20 to patients. In particular, I would like to thank Dr. Old for his vision, guidance and dedication to this project, and to his mentoring as we have moved ADI-PEG 20 from pre-clinical studies into human clinical trials.”

Dr. Old commented: “The actions of antibodies and enzymes are remarkable for their high degree of specificity, and it is this property that makes them so attractive as potential anti-cancer agents.  Although antibodies have now found broad use in cancer treatment, enzyme therapy has lagged far behind, with the one exception being the success of asparaginase in the treatment of childhood leukemia. For 10 years, LICR and Polaris have worked together to identify enzymes with anti-tumor activity, and an outcome of this collaboration is the identification of ADI, an arginine-degrading enzyme, as a highly promising therapeutic enzyme.  The anti-cancer specificity comes from the fact that arginine, a non-essential amino acid for normal cells, becomes essential for certain cancers because they lack arginine-synthesizing enzymes.  Initial clinical testing has shown that ADI has an excellent safety profile, is highly effective in eliminating arginine from the blood for extended periods, and has demonstrable anti-tumor activity in hepatocellular cancer and melanoma.”

“The current trial of ADI in patients with SCLC is particularly exciting because of the strong preclinical anti-tumor activity in SCLC models, the high frequency of arginine-dependence in SCLC, and the initial striking sensitivity of SCLC to cytotoxic agents,” added Dr. Old.  ”Because arginine dependence appears to be a characteristic of many tumor types, LICR and Polaris have decided to establish a formal partnership to explore the full potential of ADI in human cancer therapy and to use our joint strengths to identify other amino acid-degrading enzymes with anti-tumor activity. With the rapidly expanding base of information about metabolic pathways in cancer coming from deep sequencing, we look forward to finding a large number of other metabolic targets for enzyme therapy.”

About ADI-PEG 20

ADI-PEG 20 is a biologic being developed by Polaris to treat cancers carrying a major metabolic defect that renders them, unlike normal cells, unable to make arginine internally. Because arginine is one of the 20 amino acids that are essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 works by systemically depleting the external supply of arginine which causes these arginine-dependent cancer cells to die while leaving the normal cells unharmed.

Multiple cancers have been reported to have a high degree of arginine-dependency. Phase 2 clinical trials have yielded positive results in patients with hepatocellular carcinoma or metastatic melanoma, and Phase 2 trials for small cell lung cancer and mesothelioma are currently ongoing. Polaris also plans to initiate clinical studies in prostate cancer, pancreatic cancer, leukemia, lymphoma and sarcoma this year.

About Polaris Group

Polaris Group is a privately held multinational biopharmaceutical company that specializes in the research and development of protein drugs to treat cancer and other debilitating diseases. The company’s lead therapeutic, ADI-PEG 20, is advancing into a pivotal Phase 3 trial for hepatocellular carcinoma. Polaris is also investigating ADI-PEG 20 as a treatment for other arginine-dependent cancers, such as melanoma, prostate cancer, leukemia, lymphoma, sarcoma and pancreatic cancer. In addition to the ADI-PEG 20 project, Polaris is researching and developing other biotherapeutic agents and has a small molecule drug program that utilizes a rational structure-based approach to design novel compounds that inhibit the biological function of cancer-related protein targets.

For additional information please visit www.polarispharma.com

About the Ludwig Institute for Cancer Research

The Ludwig Institute for Cancer Research is a global non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery employing over 800 scientists in Branches throughout North and South America, Europe and Australia. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, LICR is actively engaged in translating its discoveries into applications for human benefit.

SOURCE Polaris Group

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http://www.polarispharma.com

New technique extends cancer-fighting cells’ potency in melanoma patients

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Posted 27 Apr 2011 — by James Street
Category Melanoma, Vaccine

Contact: Anne Doerr
anne_doerr@dfci.harvard.edu
617-632-5665
Dana-Farber Cancer Institute

BOSTON–Like brainy bookworms unprepared for the rough and tumble of post-graduation life, white blood cells trained by scientists to attack tumors tend to fade away quickly when injected into cancer patients. Dana-Farber Cancer Institute scientists, however, have developed a technique that can cause such cells to survive in patients’ bloodstreams for well over a year, in some cases, without the need of other, highly toxic treatments, a new study shows.

In a paper published in the Apr. 27 issue of Science Translational Medicine, the researchers report the results of a small, Phase I study in which the technique — a form of “adoptive immunotherapy” — was tested in nine patients with advanced melanoma. Ten weeks after starting the therapy, seven of the nine patients had more of the specially trained, tumor-hunting cells than they had started with. Three of the patients had stable disease — neither advancing nor retreating — and one had shrinkage of a tumor that had spread to the lung. Another patient experienced a complete remission, with no tumors visible on CT or PET scans. Today, 25 months after receiving the one-time therapy, he has no evidence of cancer.

The results represent the longest that the injected cells — known as anti-tumor T cells — have ever endured in cancer patients without the use of supplemental treatments — treatments that, while effective, often have harsh side effects. “The study demonstrates it is possible to maintain high levels of anti-tumor T cells in patients over a long period of time while avoiding the complications of conventional approaches,” says the study’s lead author, Marcus Butler, MD, of Dana-Farber’s Early Drug Development Center. “Our technique opens the way to therapies that produce less-toxic, long-lasting immune system attacks on cancer cells.”

The technique’s promise was further illustrated when researchers combined it with another treatment. Five patients whose disease had progressed after T cell infusions were treated with ipilimumab, a drug that boosts the cells’ anti-tumor response. Three of the patients had long-term shrinkage of their tumors, and two others had their disease stabilize. Patients who received the drug after the completing clinical trial had sizable increases in the number of anti-tumor T cells in their blood.

Melanoma skin cancers were diagnosed in more than 68,000 Americans in 2010, according to the American Cancer Society, and the numbers have been rising for more than 30 years. If detected and removed at an early stage, melanomas can usually be cured, but once the disease has spread to distant sites, the median survival time for patients is less than a year. Scientists are developing an array of novel treatment approaches to improve those odds.

Adoptive immunotherapy involves collecting T cells — natural infection- and cancer-fighters of the immune system — from a patient and exposing them to protein “antigens” found only on tumor cells. The T cells learn to recognize the antigens and to attack tumor cells that carry them. Technicians treat these “educated” T cells with a growth stimulator to increase their number and then inject them back into the patient, where they fan out to obliterate tumor cells.

Under normal conditions, the reinjected T cells die off in a matter of days. Doctors can increase their staying power by depleting patients’ blood of certain regulatory T cells that dampen the anti-tumor T cells’ response to cancer or using Interleukin 2, which spurs the growth of T cells. Both techniques can cause a host of health problems, including nausea, fever, muscle weakness, a drop in certain kinds of white blood cells, as well as other, more severe ones.

The technique developed at Dana-Farber aims to reduce those problems while giving anti-tumor T cells the stamina to persevere in the body. It involves an artificial version of cells known as antigen-presenting cells. Such cells act like tiny “FBI Most Wanted” posters: by displaying tumor cell antigens, they inform the immune system that cancer is present and needs to be eliminated. Dana-Farber scientists engineered antigen-presenting cells to produce a key molecule, known as CD83, which ensures that T cells persist for a long period of time. They also used Interleukin 15 to educate the T cells to be survivors. These educated T cells, known as memory cells, use their “knowledge” of tumor antigens to prepare them to launch a swift, powerful attack on tumor cells.

Follow-up exams of study participants showed that blood levels of educated anti-tumor T cells remained elevated many months after treatment and congregated inside the melanoma tumors. By observing how the cells function, investigators confirmed that they were indeed memory cells — and therefore the descendants of the ones that had been educated in the lab — not untrained T cells that had yet to encounter cancer cell antigens.

The researchers found that patients with the highest post-treatment levels of anti-tumor T cells did not necessarily fare better than those with lower levels. This wasn’t surprising, they say, because many tumors have developed an ability to blunt a T cell attack.

As a phase I trial, the study was primarily concerned with the safety of the technique and with its ability to produce long-lasting anti-tumor T cells in patients. The striking results in the patient who is cancer-free two years after completing therapy were unexpected, the authors say, but offer a glimpse of the technique’s effectiveness when refined and combined with other agents.

“Our next step will be to study this technique in conjunction with other therapies that can boost the numbers and effectiveness of these memory T cells,” says the study’s senior author, Naoto Hirano, MD, PhD, of Dana-Farber and the Ontario Cancer Institute in Toronto. “We will be beginning a series of clinical trials to learn which combinations work best in which patients.”

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The study was funded by grants from the National Institutes of Health, Immunotherapy Fund 1, the S. Craig Lindner Fund for Cancer Research, the Rudolf E. Rupert Foundation for Cancer Research, the Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative, Friends of the Dana-Farber Cancer Institute, the Dunkin’ Donuts Rising Stars Program, and the American Society of Hematology Scholar.

The T cells were generated in Dana-Farber’s Connell and O’Reilly Families Cell Manipulation Core Facility. The study and scientific analysis was conducted in the laboratory of Lee Nadler, MD, senior vice president of Experimental Medicine at Dana-Farber.

The co-authors of the study are Matthew Milstein, Mary Mooney, Genita Metzler, Andrew Murray, Alla Berezovskaya, Linda Drury, Lisa Brennan, RN, BSN, Marisa Flavin, Donna Neuberg, ScD, and Kristen Stevenson, Dana-Farber; Philip Friedlander, MD, Makito Tanaka, PhD, Osamu Imataki, PhD, Stephen Hodi, MD, Martin Mihm, MD, and Lee Nadler, MD, Dana-Farber and Brigham and Women’s Hospital; Elsa Velazquez, MD, Brigham and Women’s and Tufts University School of Medicine; Michael Jaklitsch, MD, and Sara Russell, MD, Brigham and Women’s; and Donald Lawrence, MD, Massachusetts General Hospital.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

Cancer break-through has man hiking up peaks instead of pushing up daisies

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Posted 25 Apr 2011 — by James Street
Category Alternative Therapies, Ethics of Science, experimental treatments, Melanoma, Molecular, Personalized, Politics and Finance of Child Cancer research, Targeted Cancer Therapy
2011-04-21 10:40:10

dead-summit-grayback-supp

Six months ago, John Murphy found out he had less than six months to live.

Undetected skin cancer had lodged in the 65-year-old retired lawyer’s hip, and the tumor was spreading cancer through his blood like dandelion fluff in the wind.

It was full-blown, stage IV melanoma. By the time Murphy saw his family doctor in October, the deadly slurry had planted tumors in both lungs. One was the size of a hockey puck.

“It was a death sentence,” Murphy said on a recent afternoon as he gasped for breath, his face gleaming with sweat.

Advanced melanoma is the worst kind of cancer. It spreads like kudzu to vital organs and has long resisted radiation, chemotherapy and every other treatment. Most patients die within nine painful months.

By November, Murphy, long been an avid hiker, was drained of energy, limping on two canes, short of breath and wincing from pain.

“I was not sure I would make it to see Christmas,” he said. “I started making up my bucket list.”

But as he told his story recently, Murphy wasn’t panting because he was fighting tumors in a hospital bed. He was panting because was hiking a steep, remote trail to one of his favorite mountain summits.

In the last three months, Murphy’s tumors have almost melted away. His pain is gone. And he is flush with renewed vigor.

“I feel incredible, like I have been given my life back and appreciate it for the first time,” he said as he trudged up the path.

Murphy has been granted what he calls a “secular miracle.” He is taking a new combination of experimental cancer drugs that leading cancer researchers describe as ground-breaking and revolutionary.

The treatment — a type of targeted drug therapy — involves no radiation, no surgery, no chemotherapy, and no harsh side effects. Patients  take a few pills per day.

The pills are packed with carefully crafted molecules designed to block certain cancer cells’ ability to divide by disrupting their mutated DNA. When the cells can’t divide, they die, and tumors start to shrink within weeks.

“It’s like you are removing the gas from the car so it can’t run,” said Dr. Bruce Chabner, clinical director of the Massachusetts General Hospital Cancer Center and  former director of cancer treatment at the National Cancer Institute. “In the past, we could only put roadblocks in its way, and it would always find a way around. … This is really game-changing.”

About 8,000 people die in the United States every year from melanoma. Murphy is one of about 200 patients nationwide participating in the clinical study of these new drugs.
The story of how the experimental drugs — called B-RAF inhibitors and MEK inhibitors — reached clinical trials stretches back almost 10 years and includes an estimated $1 billion in research. The story of how Murphy reached the trials stretches back even further.

A FAMILY CONNECTION

It starts in 1959 with Murphy’s older brother Martin.

“He is the real hero of my story,” said John Murphy. The family also includes well-known local developer Chuck Murphy.

Martin Murphy was always fascinated by medicine. In high school, he worked summers helping with autopsies at what is now St. Francis Health Center. During his junior and senior years, he would get up before dawn to take care of a gang of rats he was using to test if radioactive testosterone affected the creation of red blood cells.

“Marty was a sound sleeper but I wasn’t,” John Murphy said. “I can remember setting my alarm for four to get up so I could wake him up to take care of the rats.”

In 1959, the rat experiment won Martin Murphy first prize at the regional science fair, and then at the national science fair.

The front page of The Gazette from June 12, 1959 shows Martin Murphy being congratulated by President Dwight Eisenhower for his win.

“It was always about medicine for me, helping people,” Martin Murphy said when reached by phone recently at his home in North Carolina.

He earned a degree in experimental medicine from New York University and a handful of post doctorate degrees, all focused on cancer. Before long he was a leader in the field. He founded the Institute for Hipple Cancer Research Center in 1977 and cofounded the journal “Stem Cells” in 1981 before most people knew what a stem cell was. He also started the journal “The Oncologist.”

Today, he is respected and influential in the increasingly complex and intertwined worlds of drug developers and cancer researchers.

When John Murphy learned about the tumor in his hip, his brother was the first person he called. Martin was at a cancer congress in Italy when the phone rang at 2 a.m.

On the other end, his brother in Colorado Springs sounded drained of hope.

“John, cancer treatment today is not the same as it was when we were kids,” he said reassuringly. “It isn’t even the same as it was last year. Exciting things are happening.”
Martin Murphy started devising a strategy, plucked from his encyclopedic knowledge of the cancer world.

He got in touch with his close friend Bruce Chabner, who is also editor-in-chief of “The Oncologist.”

Chabner immediately brought up the experimental drug trial that had the potential for striking results.

If John Murphy had not had one of the leading cancer researchers as a brother, and had stayed in Colorado for treatment, he would likely have gotten chemotherapy, which might have extended his life a few months, but would have heaped on its own toxic side effects, including hair loss, nausea and fatigue.

“John Murphy was very lucky,” said Chabner, “Because Marty knew me and I knew about this very promising study.”

Within weeks, John Murphy was on his way to Boston.

But cancer patients should not think they can’t get the best care unless they have connections, Martin Murphy said.  Any cancer patient can do what he did for his brother.

“They just need to be committed. They need to work to find the very best care.”
PROMISING RESULTS

By the time John Murphy joined the experimental drug study in December 2010, work on targeted gene inhibitors had already been progressing for a decade, but they were just starting to prove their worth.

In 2002, a group of British scientists studying cancer tumors noticed that among the thousands of genetic mutations in cells, one showed up over and over:  a mutated gene called B-RAF.

“It’s one of the genes that drive cell growth,” said Dr. Donald Lawrence, Murphy’s oncologist at Mass General. “When B-RAF is mutated, it acts like a switch stuck in the ‘on’ position. Cells keep spitting and splitting out of control. What researchers began looking for is a molecule to get inside the cancer cell and shut the switch off.”

It was easier said than done. Trials of the first generation of B-RAF inhibitors started in 2004 but met with little success. The cancer continued to grow and the drugs interfered with some healthy cells as well, causing nasty side effects. All of the terminal melanoma patients taking the new drugs died.

In 2009, Lawrence began testing a more concentrated version of the drug made by the pharmaceutical giant GlaxoSmithKline, and saw something surprising. At first, tumors in terminal melanoma patients with the B-RAF mutation would melt away.

“It is almost miraculously effective,” he said. “We saw tumors shrink in 80 percent of patients in six months with very few side effects. These people get their life back.”

But within a year almost every patient relapsed and died.

In 2010, Lawrence and the other doctors leading the GlaxoSmithKline studytried something new. They theorized that when cancer cells found the B-RAF gene blocked, some started using a molecular back door known as MEK to continue to multiply.

So the researchers devised a new drug trial that would give patients the B-RAF inhibitor that had proved so effective in the short term, as well as a MEK inhibitor to block the back door.

That is the study Murphy joined a few months ago.

“It is really a new paradigm. For the first time science is starting to understand different cancers at a molecular level and devising individual treatments tailored to them,”  Lawrence said.

But will it work? Or, with the metaphorical front and back doors blocked, will melanoma find a molecular window?

“That’s what we don’t know,” said Martin Murphy. “How durable is it? How long will it last?”

ALMOST BACK TO NORMAL

John Murphy started the drug trial on Dec. 27, 2010. Each day he takes five pills: Four vitamin-sized red ones for the B-RAF and one little white one for the MEK.

“I couldn’t believe that was it,” he said. “If this study works, people will be able to fight stage IV cancer by going to the pharmacy.”

Within weeks, he noticed his strength returning. He put away one cane. Then the other.

Then he was able to snowblow his driveway. By the end of January he was snowblowing his neighbors’ driveways.

He even felt strong enough to start hiking in the mountains with friends again.

He stated calling the pills “Smith and Wesson.” They were his secret weapon.

Feb. 24 he went in for a CT scan and found that all but the biggest of his tumors had disappeared and the remaining one — once the size of a hockey puck — was smaller than a pea. Another scan last week, showed it is now just a speck.

“I’m almost totally back to normal. I do 45 minutes on the StairMaster several times a week,” he said recently.

He knows he could relapse, but the drugs have already given him months of healthy living he never though he would have.

B-RAF inhibitors could be approved by the Food and Drug Administration for general use in the next year, said Chabner, the Massachusetts General Hospital Cancer Center clinical director.

They are not a cure for cancer, Martin Murphy said, just a treatment that patients have to continue indefinitely. And they do not work on all cancers, just those caused by a B-RAF mutation. But they are a major advance.

“I don’t know if there is any bigger deal,” Martin Murphy said. “Right now the expectations of these drugs is the most important thing happening in cancer medicine worldwide.”

His brother is just happy to have his life back.

“When you thought it was all lost and you suddenly get it back, everything changes,” John Murphy said. “I hug people a lot more now.”
—
Contact the writer: 636-0223

Scientists complete whole-exome sequencing of melanoma

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Posted 16 Apr 2011 — by James Street
Category genetic research, genetic research, Melanoma, Melanoma, Personalized

From ANI

Washington, Apr 16: A team of scientists at the National Institutes of Health has become the first to systematically survey the landscape of the melanoma genome, the DNA code of the deadliest form of skin cancer.

The researchers have made surprising new discoveries using whole-exome sequencing, an approach that decodes the 1-2 percent of the genome that contains protein-coding genes.

Melanoma is the most serious form of skin cancer and its incidence is increasing faster than any other cancer.

“It is now clear that genomic analysis will have a major impact on our ability to diagnose and treat cancer,” National Human Genome Research Institute Director Eric D. Green, M.D., Ph.D., said.

“This study represents a collaboration of basic science, clinical research, genome sequencing and data analysis at its best,” he stated.

The researchers conducted a comprehensive genome analysis and explored the melanoma genome’s functional components, especially gene alterations, or mutations.

They studied advanced disease – the metastatic stage – when cells have the highest accumulation of gene mutations.

“Melanoma is one of the most challenging solid cancers to work with because it has such a high rate of mutation,” senior author Yardena Samuels, Ph.D., investigator in the Cancer Genetics Branch of the NHGRI’s Division of Intramural Research, said.

“Whole-exome sequencing will help us identify the most important changes,” Samuels said.

As a first step in the study, NHGRI researchers obtained 14 metastatic melanoma tumour samples and matching blood samples from a collection maintained at NCI.

Whole-exome sequencing of the 28 samples was performed at the NIH Intramural Sequencing Center.

Researchers eliminated from further analysis any tumour mutations that also occurred in normal tissue.

The researchers excluded from further analysis any inherited genetic alterations already annotated in such datasets as the Single Nucleotide Polymorphism database, or dbSNP, and the 1,000 Genomes Project.

Once the passenger mutations were ruled out, the team could focus on those most likely to cause melanoma.

The researchers identified 68 genetic changes that appeared to be somatically mutated at elevated frequency.

They then identified 16 genes deemed to be melanoma driver mutations, factoring for both the background mutation rate and the numbers of respective mutations found in the tumours in this study.

Of the 16, only the oncogene BRAF had ever been implicated in melanoma.

The ionotropic glutamate receptor gene, GRIN2A, was the most highly mutated of the genes newly implicated in melanoma.

It contained mutations in 33 percent of an NCI sample set and in 25 percent of a larger set of samples that combined those maintained by NCI and two other collections.

The researchers suggest that this gene is important because of its role in the signalling pathway.

“There are some indications that suggest that this is a tumour-suppressor gene, but we still need to prove that using functional studies,” Samuels said.

Next, the researchers looked for recurrent, or hot spot, mutations that occurred in multiple patient tumours.

The BRAF gene with a hotspot mutation previously implicated in melanoma led a list of nine additional genes with mutations that occurred in more than one tumour.

Mutations in seven of the nine genes caused protein-coding changes. These seven hot-spot mutations led the researchers to look precisely for these mutations in 153 additional melanoma tumours.

Mutations in one particular gene, known as TRRAP, emerged as remarkable for occurring at the exact position in six separate individuals with melanoma.

TRRAP harbours a recurrent mutation clustered in one position along the string of DNA code in about 4 percent of cases.

“These data suggest that TRRAP is a driver and probably an oncogene,” Samuels said.

Oncogenes are cancer-causing genes that enable the cell to survive despite stressful conditions, rather than die off normally.

“This was one of the most important discoveries in the study since we never expected to identify novel hot-spot mutations,” she said.

Lastly, the researchers used cell signalling pathway analysis, identifying glutamate signalling as a pathway involved in melanoma.

“We are starting to explore what mutations do to the glutamate pathway,” Samuels said, while noting that ongoing research will entail complex biochemistry.

The study has been published in the April 15, 2011, early online issue of Nature Genetics.

Copyright Asian News International/DailyIndia.com

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