During the 2008 Annual Meeting, The ASCO Cancer Foundation presented
Advanced Clinical Research Awards (ACRAs) to four investigators for innovative research initiatives in sarcoma, breast cancer, and hematological malignancies. Each recipient’s institution will receive $450,000 to be disbursed during the next three years through generous grants from The Sarcoma Foundation of America and Capon Family, ARIAD Pharmaceuticals, Inc., Genentech BioOncology™, and The Breast Cancer Research Foundation.
Raphael Rousseau, MD, PhD—head of the pediatric translational research program at the Institut d’Hematologie Oncologie Pediatrique in Lyon, France—will use the ACRA funding to produce a clinical-grade compound that uses his nanoparticle technique in an approved pharmaceutical laboratory where surgeons can assess the improved visualization of tumor margins and lung metastases using an infrared camera. His ACRA-winning abstract, “Nanoparticle-based targeting tumor neoangiogenesis to improve surgical resection of primary tumor and lung metastasis in advanced osteosarcoma,” describes a new approach that physicians can take against osteosarcoma, a disease that affects mostly adolescents. Currently, there is no intraoperative technique that allows surgeons to “see” the outlines of tumors they are trying to remove. Consequently, they must use large margins during surgery—a technique that Dr. Rousseau indicates can have a negative effect on bone reconstruction and hinder the recovery of the patient.
Dr. Rousseau and his research team have developed a concept that would help surgeons identify a tumor’s precise boundaries and limit the amount of healthy tissue they sacrifice when eliminating it. Using an animal model of metastatic osteosarcoma, the team used ligands of receptors that are overexpressed by tumor neovessels to deliver fluorescent molecules directly to tumor cells and light the path for surgical removal. Dr. Rousseau explained that this approach also may help surgeons localize micrometastases in the lungs and remove them before they become too large for surgical excision. He is hopeful that this technique will be useful across the oncology spectrum. Researchers are now testing this approach in preclinical models of colon cancers, prostate cancers, and thyroid cancers, according to Dr. Rousseau.
Scott M. Schuetze, MD, PhD, of the University of Michigan, received an ACRA in Sarcoma that will allow him to explore whether there is a specific molecular signature in some types of sarcomas that could be used to help preselect patients most likely to benefit from treatment with drugs blocking the mammalian target of rapamycin (mTOR) pathway in combination with conventional chemotherapy, such as alkylating agents.
The number of drugs with significant activity for the treatment of advanced sarcoma is scarce, according to Dr. Schuetze, and he is working to develop comprehensive solutions to this problem. His clinical research has focused on identifying new agents with promising antisarcoma activity through participation in cooperative or multi-institutional trials. He explained that drugs targeting specific growth pathways, such as intracellular signaling through tyrosine kinases or the mTOR, have modest activity in sarcoma when used alone, except for the c-kit and platelet-derived growth factor receptor inhibitors in gastrointestinal stromal tumor and dermatofibrosarcoma protuberans.
“Preclinical studies suggest that combining these newer agents with more traditional cytotoxic chemotherapy may augment the antitumor activity of the newer agents,” he said. “The standard chemotherapy for treatment of advanced sarcoma—doxorubicin, ifosfamide, and gemcitabine combined with docetaxel—is rather toxic to patients, and treatment is limited by cumulative toxicity.” Dr. Schuetze is interested in uncovering treatments with antisarcoma activity that are “easy for patients to take, preserve good quality of life, and that can be administered over a prolonged period of time.”
Mark J. Levis, MD, PhD, Assistant Professor of Oncology at Johns Hopkins University School of Medicine, believes that his award-winning research proposal, “Incorporating a FLT3 inhibitor into AML therapy,” has the potential to represent a change in the way researchers start the development of a new oncology drug.
“What we are trying to do with this project,” he explained, “is completely change the way early phase oncology trials are done. In developing a targeted therapy for leukemia, we are trying to implement a method of identifying not just the safe and tolerable dose of a targeted drug, but the dose that will inhibit the target in a manner that best recapitulates how the drug was used in the laboratory.”
“Oncology,” he noted, “is a field treating diseases in which this signaling has usually gone awry, so the problems confronting us in treating cancer can at least be approached by manipulating cell signaling.”
Dr. Levis emphasized the importance of translational research to future advances in cancer care. “I think one of the biggest reasons we have had such a low success rate getting oncology drugs beyond early phase trials all the way to approval has been the lack of collaboration between scientists and clinicians,” he said. “Scientists do not always understand that a human being is not just a large tissue culture dish with arms and legs. Clinicians, on the other hand, often lose sight of the intended biologic consequence of the drug they are studying in their zeal to conform to rigid trial designs.”
Through his research,
Lajos Pusztai, MD, PhD, of M. D. Anderson Cancer Center, will examine putative response markers in prospectively conducted phase II trials, similar to the testing of novel drugs. In his study, he will demonstrate two strategies for discovering molecular predictors of response to therapy that may be used to select patients for treatment.
The first approach will compare molecular features of cancers with known clinical responses, and the second will focus on examining putative predictors in preclinical models and will test them in human clinical trials. “The current proposal aims to complement our research portfolio and start a program to test a priori defined candidate response markers in metastatic disease,” Dr. Pusztai wrote in his summary of the study’s background.
Three distinct genomic predictors for dasatinib therapy will be tested, including a 161-gene signature developed from cell lines, a 46-gene src pathway activity signature, and a 19-gene dasatinib target index. Dr. Pusztai and his research team predict that molecular markers that are predictive of response in a cancer cell line or other experimental models also will predict response in human breast cancer. The goal of this trial is to identify predictors with clinically relevant positive predictive values. “We envision a broad program that will simultaneously evaluate multiple markers and several different drugs,” Dr. Pusztai said.
