|
|
              
|
by Bruce Shriver and Tom Swartz
ARIAD Announces Comprehensive Phase II Data for AP23573 at ASCO At the recent 2006 annual meeting of the American Society of Clinical Oncology (ASCO) in Atlanta, Georgia, ARIAD announced that AP23573 – its novel mTOR inhibitor – demonstrated efficacy and was well tolerated as a single agent in a multi-center Phase 2 trial in metastatic and/or unresectable soft-tissue and bone sarcomas involving 212 patients, at least 90% of whom had progressive disease. The primary endpoint of the trial – evidenced by clinical-benefit response rates – was achieved in the three most prevalent types of sarcoma (i.e., bone sarcoma, leiomyosarcoma and liposarcoma). Treatment with AP23573 more than doubled progression-free survival when compared to historical control data published by the European Organization for Research and Treatment of Cancer (EORTC). The following results were presented by Dr. Sant Chawla, co-principal investigator of the study, in an oral session during the 42nd annual meeting of ASCO:
Based on the Company’s ongoing interactions with the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA), ARIAD plans to conduct a randomized, worldwide Phase 3 clinical trial of oral AP23573 in patients with advanced sarcomas.
The objectives of this retrospective study were: (1) to analyze the relation between dedifferentiated liposarcomas (DDL) and tumors previously diagnosed as malignant fibrous histiocytomas (MFH) (MFH is no longer considered a homogeneous entity, but rather as the common morphologic appearance of various subtypes of sarcomas); (2) to trace the evolution of liposarcomas, and (3) to assess the consequences of dedifferentiation. Between 1974 and 2001, 86 patients with retroperitoneal liposarcoma (61 patients) or MFH (25 patients) underwent surgery at Institut Bergonie in Bordeaux, France. A histologic review was performed and tumors reclassified as well-differentiated liposarcoma (WDL) or DDL were retained for further clinicohistologic study. Subsequently, initial presentation and all recurrences were analyzed. The 61 liposarcomas consisted of 21 WDLs and 35 DDLs; 17 MFHs were reclassified as DDL. In all, approximately half of the retroperitoneal liposarcomas and MFHs were found to be DDLs. The DDLs presented with a smaller size (20 cm vs.30 cm; P = .05) but a lower rate of complete resection (72% vs.90%; P = .015) and remission (72% vs. 100%; P = .0015). Dedifferentiated recurrence was evidenced in 7 WDLs. Ten DDLs presented with metastatic evolution. DDLs demonstrated a tendency toward lower rates of 5-year overall survival (55% vs. 82%; P = .075). Thus, the authors conclude that most occurrences of retroperitoneal liposarcomas and MFHs are in fact DDLs and dedifferentiated recurrence of WDLs is frequent. Also, retroperitoneal DDLs present a lower rate of complete remission than WDLs and a risk of metastatic recurrence. Therefore, extensive histologic analysis of WDLs is required to identify an undifferentiated component and avoid misdiagnosis of DDL.
New Understanding Of Ewing's Sarcoma Suggests Novel Treatment Strategy Using molecular and cell-based models, researchers at Georgetown University Medical Center have refined the picture of how a cancer-promoting protein associated with Ewing's sarcoma functions. And in the process, they have hit upon a possible strategy for treatment. In the June 1st issue of the journal Cancer Research, published by the American Association for Cancer Research, the researchers report that the oncoprotein, EWS-FLI1, teams up with a helicase protein that bends the shape of RNA, and together they work to promote or repress transcription of various other proteins, leading to cancer development. But because it is not possible to directly shut down helicase proteins, given their vital general role in protein transcription, and given that no one has figured out how to clinically inactivate EWS-FLI1 alone, the researchers propose driving a wedge-like drug between the two proteins that would eliminate their interaction. "Proteins are three-dimensional structures, and the space between EWS-FLI1 and the helicase might be targetable by a small molecule that keeps the proteins apart," says the study's lead author Jeffrey Toretsky, M.D., an associate professor in the departments of Oncology and Pediatrics at the Lombardi Comprehensive Cancer Center. "It could render EWS-FLI1 harmless while not affecting its partnering helicase protein." Toretsky adds that the findings may also help explain the workings of a number of difficult-to-treat sarcomas that are caused by the same sort of genetic rearrangements seen in Ewing's sarcoma. "Understanding the molecules EWS-FLI1 interacts with may provide insights into similar diseases," he said. "Very little work has been done to study the functional partners of these translocation proteins, and this study may offer a new research approach." Ewing's sarcoma is caused by a translocation between two chromosomes which fuses the EWS gene from chromosome 22 to the FLI1 gene of chromosome 11. This fusion produces the EWS-FLI1 fusion protein which is only found in tumors. This translocation is present in 95 percent of tumors, according to Toretsky, a recognized expert on Ewing's sarcoma. Chromosomal translocations are the cause of many sarcomas and leukemias, and the resulting fusion proteins represent targets for new therapies. In Ewing's sarcoma, the proteins that are created from chromosomal translocations are unique and only occur in the tumor cells. Therefore, fusion protein produced by translocation in Ewing's Sarcoma represents "an ideal target" for therapy, according to Aykut Üren, MD, PhD, assistant professor of oncology and a co-author on the paper. Previously published animal studies using "antisense" molecules have indeed shown that when the EWS-FLI1 is inactivated, Ewing's Sarcoma does not develop. But antisense, which modifies gene expression, is technologically inappropriate for human therapy, and to date, no one has been able to design a drug that would shut down EWS-FLI1 in humans. "The fusion protein is known to be oncogenic, but we suspected that it must work with other molecules, and these molecular interactions could offer us opportunities for treatment," Toretsky said. To find out if their hypothesis was true, the research team utilized a virus that displayed random, but identifiable, protein sequences and mixed the viruses with EWS-FLI1. "We wanted to see what viruses stuck to the EWS-FLI1 protein," Toretsky said. They found a certain peptide sequence attached to EWS-FLI1 in every experiment they conducted, and a search of the Human Genome database showed these sequences belonged to RNA helicase A (RHA), a common helicase not known to be oncogenic. They then conducted a number of rigorous studies to prove that EWS-FLI1 and RHA did indeed bind to each other in a complex. Furthermore, when EWS-FLI1was expressed along with RHA, the cells demonstrated increased hallmarks of cancer development. "The two proteins appear to work together in order for EWS-FLI1 to have maximal oncogenic potential," Toretsky said. "Since EWS-FLI1 needs RHA, our goal is to keep them apart." To access the abstract of the original article click here.
Cryoablation refers to the application of extreme cold to destroy diseased tissue, including cancer cells. In surgery, the term percutaneous pertains to any medical procedure where access to inner organs or other tissue is done through the skin, as opposed to using an open approach where the organ or tissue are exposed typically through the use of a scalpel. The investigators of this study sought to determine whether percutaneous cryoablation of pulmonary metastases might be a useful therapy for nonsurgical candidates. The procedure was performed after local anesthesia for 35 tumors in 20 patients (12 male and 8 female patients; mean age, 57 years). The primary end point was the safety and feasibility of cryoablation, and the secondary end point was tumor control assessed by follow-up dynamic computed tomographic scanning performed every 3 months. The investigators found that of the 22 sessions of cryoablation, pneumothorax (accumulation of air in the pleural cavity) occurred in 11, hemoptysis (the expectoration of blood) occurred in 8, and there was 1 case of phrenic nerve palsy (paralysis). The mean hospital stay was 2.6 days. There was local recurrence of 7 (20%) tumors in 7 (35%) patients during a 9- to 28-month (median, 21 months) follow-up period. One-year survival according to the Kaplan-Meier method was 89.4%. The investigators thus conclude that percutaneous cryoablation therapy for metastatic lung tumors is feasible and minimally invasive, with satisfactory local control.
A higher, investigational starting dose of Gleevec® (imatinib mesylate)* tablets can improve outcomes for high-risk patients with advanced Kit-positive gastrointestinal stromal tumor (GIST) expressing exon 9 mutation, according to new findings from the largest clinical trial to evaluate the drug's effects by mutation. The clinical trial, an EORTC (European Organization for Research and Treatment of Cancer) phase 3 study, compared two doses of Gleevec in patients with unresectable and/or metastatic Kit (CD117) positive GIST. While the majority of patients derived benefit from taking 400 mg/day of Gleevec, the study showed that patients whose tumors expressed a mutation on a certain gene segment called exon 9 had significantly superior progression-free survival (P =.0013) when administered Gleevec at the investigational dose of 800 mg/day. In this study, investigators analyzed data from a recent randomized EORTC Phase III trial comparing two doses of Gleevec (400 mg/day vs. 800 mg/day) in patients with unresectable and/or metastatic Kit-positive GIST, to assess whether tumor genotype correlated with the dose-dependent clinical response to Gleevec. Pre-treatment samples of GISTs from 377 patients enrolled in the clinical trial were analyzed for mutations of Kit and platelet-derived growth factor receptor alpha. The presence of a Kit exon 9 mutation was the strongest adverse prognostic factor for response to Gleevec, increasing relative risk of progression by 171% (P <.0001) compared to Kit exon 11 mutations. In patients whose tumors expressed a Kit exon 9 mutation, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P =.0013), with a reduction of the relative risk of 61%.
Quick Notes Scientists Tie Several Cancers to Common “Oncogene Engine” Researchers at Dana-Farber Cancer Institute report that a common “oncogene engine” – a small family of malfunctioning cell growth switches – drives several seemingly unrelated, lethal forms of cancer, including malignant melanoma. The finding suggests that it may be possible to attack these different cancers with the same therapy. Reporting in the June issue of Cancer Cell, the scientists showed that a small transcription factor family, made up of several proteins that control the activity of key growth genes, functions abnormally in malignant melanoma, two forms of soft-tissue sarcomas, and a type of kidney cancer that mainly affects children. Still other cancers sharing the same causative mechanism may yet be found, the scientists said.
The Roulette Wheel: An Aid to Informed Decision Making From the abstract of this article by Dr. Jerome Hoffamn at el. "The old model of physician as authority figure dispensing advice and recommendations in the expectation that these will be followed precisely by patients has, for the most part, fallen out of favor. Such an image of physician as benevolent (or beneficent) dictator has been challenged by concern for patient autonomy, and shared decision making (SDM) has largely been adopted as an ideal way for physicians and patients to join together whenever there are decisions that need to be made about management of health care issues. SDM, in its best form, requires an informed and skillful physician, who is aware of the best available scientific evidence from clinical research, and is expert at communicating with patients in a meaningful, comprehensive, and non-distorted manner." Click here to access the entire article.
Image Screening and Wellness: What to Tell Patients and Referring Physicians CME/CE 06/07/2006 One aspect of "well care" that has captured the professional and public imagination has been screening of apparently healthy individuals for preclinical forms of serious diseases."
ASCO's Sarcoma Center
V3N3 ESUN Copyright © 2006 Liddy Shriver Sarcoma Initiative.
|
