The research efforts of the Department of Medical Oncology & Therapeutics Research contribute immensely to the progress of the Developmental Cancer Therapeutics Program of City of Hope. This multidisciplinary program spans basic, translational and clinical research by fostering close collaborations among researchers. The overarching long-term goal of the Developmental Cancer Therapeutics Program is to develop more effective and less toxic treatments for cancer. The scientific agenda of the department focuses on the development of novel therapeutic agents for all histologic types of cancer. Faculty members of the department have assumed leadership in bringing innovative cancer therapies in the clinic by designing investigator-initiated, hypothesis-driven clinical trials complementing the industry partners cancer drug development activities. The department's clinical research endeavors are largely responsible for the high patient accrual to the overall cancer center therapeutic trials.

Highlights of Current Efforts
The phase I and phase II California Cancer Consortium (CCC) programs (U01 and N01 grants), funded by the National Cancer Institute Cancer Treatment Evaluation Program, utilizes the combined expertise of City of Hope, University of Southern California and University of California, Davis in the areas of molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging and bioinformatics to conduct innovative, laboratory-directed phase I developmental and pharmacokinetic studies that focus on:
  1. agents that target genetic or epigenetic abnormalities in cancer cells;
  2. agents that target signal transduction pathways, the cell cycle and host/tumor interactions;
  3. agents that are potentially active in hematologic malignancies;
  4. agents developed through CCC investigator-initiated RAID projects;
  5. examination of special patient populations for the clinical pharmacology of targeted anticancer agents whose therapeutic effects may be altered because of abnormal organ function or because of inherited differences in genes controlling drug disposition and activity;
  6. identification of new and informative laboratory correlates of biologic activity and drug resistance and exploration of novel functional endpoints of tumor response, progression, and clinical benefit for patients entered on the phase I clinical trials of the CCC.
Principal investigators: Edward Newman, Ph.D., and Robert Morgan., M.D.

The City of Hope  Clinical Oncology Research Career Development Program , a National Cancer Institute K12 Training Program, aims to develop a new generation of clinical oncologic investigators capable of translating basic advances in cancer biology into novel strategies for the diagnosis, therapy and prevention of malignant disease. This multidisciplinary effort will be available to outstanding surgeons, radiation oncologists, pathologists, pediatricians, and internists who have completed their fellowship training in oncology no more than three years previously, and who are appropriate for appointment to the faculty of City of Hope. The curriculum of the City of Hope K-12 Training Program involves both didactic and hands-on experience in basic science, laboratory research, biostatistics and clinical investigation.

Clinical research through the Southwest Oncology Group cooperative grant continues to be an important part of the Departments research portfolio. Faculty members of the department have a long-standing commitment to this cooperative grant as demonstrated by their leadership in the group, involvement in protocol development, meeting attendance and enrollment of patients that exceeds the national annual baseline on clinical trials. (Principal investigator:Joanne Mortimer, M.D.)

Specialized programs integrating basic and clinical research that will establish the best pattern of care for cancer patients aged 65 are the focus of the Cancer and Aging Research Program . Efforts include developing an assessment tool that improves oncologists ability to anticipate chemotherapy toxicity, predicting overall outcomes and developing interventions to improve outcomes among older patients. (Principal investigator: Arti Hurria, M.D.)

Studies in our laboratory revealed that of several vegetable extracts tested, mushroom extract, particularly from Agaricus bisporus, or the common white button mushroom, contain phytochemicals that suppress estrogen biosynthesis via aromatase inhibition. The first clinical trial to test the aromatase inhibition capability of mushrooms in human subjects is now under way in postmenopausal breast cancer survivors. (Principal investigator: Melanie Palomares, M.D., M.S.)

Several multi-institutional studies on assessing biomarkers associated with targeted therapy in nonsmall cell lung carcinoma focused on the expression of several human tissue kallikreins, a family of 15 secreted serine proteases, are now currently accruing patients. (Principal investigator:Karen Reckamp, M.D., M.S.)

Our basic science collaborators have evaluated the effect of an extract of white button mushroom on prostate cancer cell lines in vitro and vivo. We determined that mushroom extract significantly inhibits cell proliferation in a dose-dependent manner in all cell lines tested. Taken together with research from other laboratories, our results support the concept of testing white button mushroom as a dietary component that may aid in the treatment of asymptomatic men with biochemical recurrence of prostate cancer. (Principal investigator: Przemyslaw Twardowski, M.D.)

Despite recent advances in molecularly targeted therapies for cancer, primary brain tumors, particularly high-grade gliomas, remain a serious clinical challenge for oncologists. A major obstacle to successful pharmacologic treatment of central nervous system tumors is the blood-brain barrier (BBB), which prevents most anticancer agents from entering the central nervous system. Another key reason for the lack of success in treating gliomas is their diffuse and highly infiltrative nature; no clear border exists between tumor and normal brain. Glioma cells disseminate from the primary site, forming microtumor foci throughout the brain that often hide behind an intact BBB. To make a significant impact on the survival of brain tumor patients, new therapies must not only be able to navigate through or around the BBB, but they should also specifically target the invasive tumor cells that escape currently available treatments. The effectiveness of gene therapy has been limited by the inability of the carrier cells to deliver therapeutic agents with sufficient distribution throughout primary and distant tumor sites. Human neural stem cells (NSCs) hold great promise for glioma therapy due to their inherent tumor-tropic properties. They can track to infiltrative tumor cells and localize to distant microtumor foci. When modified to express a therapeutic transgene, NSCs can serve as vehicles for drug delivery, in effect circumventing the BBB to deliver a concentrated amount of active drug directly to tumor cells while minimizing toxicity to normal brain tissue. (Principal investigator: Jana Portnow, M.D.)

Liposarcomas are the second most common soft-tissue sarcoma. The use of HIV protease inhibitors is associated with the HIV protease-induced lipodystrophy syndrome. This syndrome is characterized by peripheral fat wasting, central fat accumulation, insulin resistance and hyperlipidemia. Preclinical studies suggested alteration of sterol regulatory element binding protein-1 a lipogenic transcription factor, in the development of this syndrome. Based on the biology of this syndrome and its proposed pathophysiology, we hypothesized that HIV protease inhibitors might serve as novel, targeted agents against liposarcoma. As a result of these preclinical studies, we have developed a Food and Drug Administration-funded clinical trial of nelfinavir for recurrent liposarcomas. (Principal investigator: Warren Chow, M.D.)

New Developments
Strategic, integrated programs on Intracerebral Microdialysis in Rats Bearing Orthotopic Glioma and Treated with Genetically-modified Neural Stem Cells: The central hypothesis of this pilot study by collaborators from the Developmental Cancer Therapeutics Program and the  Hematologic Malignancies (HM) Program of City of Hope, and with combined expertise in intracerebral microdialysis, pharmacology and NSCs, is that NSC-mediated expression of high levels of CE will convert CPT-11 to SN-38 extracellularly and that the SN-38 will diffuse into adjacent invasive brain tumor cells and eradicate them. Our objective within this proposal is to use intracerebral microdialysis to assess whether SN-38 is produced in vivo in the area of tumor after intracranial delivery of NSCs and systemic administration of CPT-11. (Principal investigators: Jana Portnow, M.D., Karen Aboody, M.D., and Timothy Synold, Pharm.D.)

Preclinical studies on renal cell carcinoma (RCC) therapeutics are under way in collaboration within the laboratories of Eleanor Hua Yu, Ph.D., and Stephen J. Forman, M.D. STAT3 has been identified as a downstream target of Sunitinib and shown that Sunitinib directly induces RCC apoptosis and growth arrest in a STAT3 dependent manner. These findings will have impact on the future design of new strategies on the use of Sunitinib for RCC patients.