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Odds & Ends Abstracts by Tom Swartz
In this issue:
Heart failure associated with sunitinib malate Sunitinib malate is a novel multitargeted receptor tyrosine kinase inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. This report describes the development of heart failure in cancer patients who received this novel agent. A retrospective study was conducted at M. D. Anderson Cancer Center during a 1-year period on patients who received sunitinib and developed heart failure. The RESULTS were as follows: During 2006, 6 of 224 (2.7%) patients who received sunitinib developed heart failure (HF) that resulted in substantial morbidity and, in some cases, mortality. Symptomatic heart failure occurred soon after initiation of sunitinib (mean onset 22 days after initiation), was associated with decline in cardiac function and elevations in blood pressure, and was not completely reversible in most patients, even after termination of sunitinib therapy. The authors CONCLUDE: These observations suggested that sunitinib-associated heart failure may represent a potentially serious toxicity and they underscore the need for careful monitoring of cardiac function and aggressive control of hypertension in these patients. Studies to elucidate potential mechanisms of heart failure and left ventricular dysfunction resulting from treatment with sunitinib are necessary to develop strategies for prevention and treatment of this complication.
Management of Cancer Pain: Basic Principles and Neuropathic Cancer Pain Pain is one of the most common symptoms in patients with cancer; it occurrs in as many as 90% of patients during their illness. Pain is a complex phenomenon, which can be exacerbated by numerous other factors. This paper discusses the common strategies for the management of cancer pain in general and also neuropathic cancer pain. A copy of this report can be purchased using the above link.
Parenting Stress in Pediatric Oncology Populations The experience of childhood cancer can be one of the most severe stressors that parents endure. Studies using illness specific measures of parental stress indicate that moderate-to-severe parenting stress is quite common in the first year of childhood cancer treatment, and as many as 5% to 10% of these parents go on to develop posttraumatic stress disorder. This review of the literature suggested that although parenting stress symptoms may be relatively transitory for most parents dealing with childhood cancer, the impact of these stress symptoms on parent and child functioning is substantive and worthy of therapeutic attention.
Sarcoma Advocate Claims Inquiry Into Fast-tracking of Avastin Could Hurt Cancer Drug DevelopmentSenator Chuck Grassley (R-Iowa) recently requested that the Government Accountability Office investigate whether the FDA acted appropriately in granting "accelerated approval" to the cancer drug Avastin. Mark Thornton, MD, president of the Sarcoma Foundation of America and a former medical officer in FDA's Office of Oncology Drug Products, now argues in a Wall Street Journal Opinion Piece that the inquiry, "will have a catastrophic effect on America's ability to develop new drugs."
The drug, Avastin, was granted accelerated approval for treating women with metastatic breast cancer after showing early evidence of an effect on the "surrogate endpoint" known as "progression-free survival," according to Thornton.
Grassley "implied in his GAO request that something sinister occurred during the FDA's premarket deliberations and that surrogate endpoints were the new bogeyman," Thornton writes, adding, "Nothing could be further from the truth." He states that evaluating a cancer drug's effect on surrogate endpoints, as opposed to impact on overall survival, to potentially allow "expedited" approval of drugs has "won near-universal acceptance within the cancer community."
Grassley "is demanding a full-scale review of each and every product ever approved and is asking for a re-judgment by GAO 'to ensure that drugs approved on surrogate endpoints are both safe and effective,'" according to Thornton. However, Thorton claims the senator's "bully tactics" could cause cancer drug development to "slow to an absolute crawl" because the "extremely cautious and protective" FDA "will respond to such intimidation by being even more protective," Thornton writes.
He adds, "U.S. cancer drug development stands on a precipice overlooking a new dark age in which each new product's development is longer and costlier than the last," and drug makers may "decide it is not financially viable to even bother developing new drugs." Thornton writes, "Mr. Grassley's legacy could be thousands of additional cancer deaths" (Thornton, Wall Street Journal, 5/29).
Better Cancer Cell–Specific Therapies In the May 2008 edition of The Oncologist (Vol. 13, No. 5, 593-595) an editorial, "The Long and Winding Road to Better Cancer Cell–Specific Therapies", recounts some of the successes in treatment using cancer cell–specific compounds. The author argues that we should continue to further unravel the molecular mechanisms underlying malignancies since it is only by such efforts that we will learn which targets to aim for and how to hit them most effectively. Click the above link to access the entire article.
Potential Viral Therapy Weapon Is Safe And Effective In Mouse Study Combining a herpes virus genetically altered to express a drug-enhancing enzyme with a chemotherapy drug effectively and safely reduced the size of highly malignant human sarcoma grafted into mice. This new finding may add to the growing arsenal of so called oncolytic viruses under development as novel cancer treatments.
"Our study shows the chemotherapy drug cyclophosphamide (CPA) enhances the anti-tumor effectiveness of the oncolytic virus rRp450 in mice carrying aggressive human sarcoma, resulting in significant tumor shrinkage," said Timothy P. Cripe, M.D., Ph.D., a physician and researcher at Cincinnati Children's and the study's corresponding author. "Just as important is the fact that the combination of rRp450 and CPA appears to be well tolerated, because non-cancer bearing mice treated with the therapy survive long term. It will take some time to continue developing this approach before its potential to be tested in clinical trials, but our results are encouraging and warrant further study."
Dr. Cripe's research team injected sarcoma tumors in mice with rRp450, in which a normally occurring gene was deleted and replaced with a gene that encodes an enzyme to activate chemotherapy drugs called oxazophosphorines, including cyclophosphamide (CPA). Previous studies have reported the rRp450 virus kills cancer cells by causing their cell membranes to erupt, and that the virus helps the anti-tumor effects of CPA.
In the current study, rRp450/CPA treatment significantly shrunk a form of human rhabdomyosarcoma. When the grafted tumors reached 200-500mm in size, seven mice were treated twice over eight days with a combination of rRp450/CPA, with rRp450 administered by direct tumor injection 24 hours prior to CPA. The researchers noted significant tumor shrinkage with one animal perishing 20 days following initial injection, two more within 30 days, two within 40 days and the last two mice surviving nearly 50 days post treatment.
The investigators also confirmed the anti-tumor effect of rRp450 treatment alone in mouse models of human cancers rhabdomyosarcoma and neuroblastoma, where they observed significant tumor shrinkage in 13 of 13 injected tumors. Treatment with CPA alone in these models showed limited anti-tumor effectiveness. In a control group of tumor-carrying mice treated with a placebo, all died within 10 days of injection.
Also noteworthy in this study is documentation of the treatment's potential safety, specifically toxicity to nerve tissues. Most research of oncolytic herpes simplex viruses (oHSVs) has so far been limited to those engineered by deleting both copies of the neurovirulence gene that prompts wild-type HSV-1 virus to spread and invade the nervous system. Deleting both copies disarms most of the virus' disease-spreading properties while retaining its ability to damage targeted cancer cells.
The rRp450 virus is different because it retains both copies of the virulence gene but is attenuated by deletion of a different gene. Earlier preclinical studies showed that deleting just the single gene increases rRp450's ability to degrade cancer cells, but until the current study little had been known about whether a virus with a single-gene mutation would retain neural toxicity to the recipient.
The researchers did note that tissue samples tested during the study retained some viral genetic material, notably DNA fragments, although there were no signs of active disease. Because mice received combined rRp450/CPA only once during the toxicity part of the study, safety tests based on repeated dosing are still needed, and would be necessary to support a multi-dose clinical trial, the researchers said.
"Based on these findings and other preclinical studies, we expect oncolytic viral therapy will be one additional treatment modality available in the future for oncologists," Dr. Cripe said. "The challenge over the next decade will be determining which viruses work best for which cancers, at what doses, schedules, routes of administration, and in what combinations with other treatments."
Researchers in Australia Pinpoint the Function of a Potent Cancer Gene Researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Australia have pinpointed the function of a potent cancer gene. The gene, known as "ERG", has long been associated with a range of cancers including leukemia and sarcoma. American scientists showed in 2005 that ERG is mutated in more than half of all prostate cancers. It was unclear, however, what function ERG normally performs in the human body and why it is so carcinogenic when mutated.
The team at WEHI has now demonstrated that ERG's usual role is to regulate the activity of blood stem cells. Without ERG, these cells cannot divide normally and the body fails to generate the trillions of blood cells that are required each day to carry oxygen and fight infection.
The study suggests that ERG causes cancer by convincing normal cells to behave like stem cells, triggering unrestrained growth and expansion. The findings offer hope that the targets of ERG might now be open to identification, which in the future might lead to new drugs that shut down the proliferation of cancer cells.
Ludwig, Joseph A, Current Opinion in Oncology. 20(4):412-418, July 2008. Abstract: Purpose of review: As the second most common bone malignancy in children and adolescents, Ewing sarcoma family tumors represent almost 3% of pediatric cancers. Multidisciplinary management of patients with Ewing sarcoma has substantially improved the likelihood of survival for patients with localized disease. Yet, the prognosis of those with metastatic or recurrent disease has changed very little over the past three decades. Here, we focus on the current state-of-the-art in the diagnosis, staging, and treatment of Ewing's sarcoma and then highlight the most likely biological targets amenable to future therapies.
Recent findings: An improved understanding of the molecular biology of Ewing's sarcoma has led to clinical trials testing novel therapies specifically designed to thwart critical pathways responsible for this malignancy. Insulin-like growth factor-I receptor targeted monoclonal antibodies are just one example that has shown promise in early phase human clinical trials.
Summary: With an improved understanding of the genome, transcriptome, proteome, and other '-omic' events that promote and sustain Ewing pathogenesis, the use of nascent biologically targeted therapeutics is on the horizon. Understanding how and when to integrate such therapies into clinical practice, although challenging, may lead to a paradigm shift towards more personalized therapy.
New targets for therapy of sarcoma Magenau, John M; Schuetze, Scott M, Current Opinion in Oncology. 20(4):400-406, July 2008. Abstract: Purpose of review: Systemic treatment options for advanced sarcoma remain limited. Emerging trends exploring targeted therapy for the treatment of sarcoma are reviewed here.
Recent findings: Effective treatments for metastatic sarcoma after the failure of front line regimens, such as doxorubicin, ifosfamide, and gemcitabine with docetaxel, are clearly limited. Translational research has identified a significant proportion of sarcomas with characteristic molecular changes potentially amenable to targeted therapy. Aberrant signaling of mammalian target of rapamycin and tyrosine kinase pathways have been focal points of recent research. Early trials investigating biologic inhibitors of these pathways have yielded varied clinical results. Agents targeting stem cell factor receptor (C-KIT), platelet-derived growth factor receptor, mammalian target of rapamycin, and vascular endothelial growth factor receptor have all shown efficacy to some degree in advanced sarcoma. The insulinlike growth factor-1 receptor is a potentially important target for sarcoma treatment based on early clinical results.
Summary: Sarcomas are a heterogeneous group of tumors and targeted agents likely have a long-term role in their treatment. Identifying critical pathways in sarcomagenesis, susceptible subtypes and developing novel combinations remain the focus of future research.
Oncolytics Biotech Inc. Present Positive Phase II Sarcoma Trial Results at ASCO Annual Meeting On June 2nd, Oncolytics Biotech Inc. announced interim results of a Phase II study of intravenous REOLYSIN(R) in patients with sarcomas metastatic to the lung at the American Society of Clinical Oncology (ASCO) annual meeting. The presentation, entitled "A Phase II Study of Intravenous REOLYSIN (Wild-type Reovirus) in the Treatment of Patients with Bone and Soft Tissue Sarcomas Metastatic to the Lung" was delivered by Dr. Monica Mita, the study principal investigator.
The interim results demonstrate that the treatment has been well tolerated to date, with 8 of 16 evaluable patients experiencing stable disease for periods ranging from two to more than ten, 28-day cycles. As previously announced by Oncolytics, the third patient treated in the study was demonstrated to have stable disease by RECIST criteria for more than six months as measured by CT scan. A PET scan taken at the same time showed that any residual mass was metabolically inert.
"These very encouraging data have increased our commitment to the thorough investigation of this exciting, unique, truly targeted agent," said Dr Francis Giles, Director of the Institute of Drug Development at the University of Texas Health Science Center.
"We feel privileged to participate in this study and to be able to offer this therapeutic option to our patients," said Dr. Mita. "Patients have tolerated the treatment well and seem to have disease control up to several months, which is encouraging for patients with advanced refractory sarcoma."
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