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Research Program
Experimental Therapeutics

Program Summary
Conventional cancer therapies remain less than optimal for treating the majority of common malignancies. Confounding the issue of efficacy is the fact that standard cytoreductive treatment modalities have the highly undesirable property of indiscriminately killing normal as well as tumor cells. Hence, the challenge for clinical investigators is to move cancer therapy away from the use of highly toxic, non-selective drugs and develop rational approaches that lead directly to selective cancer cell death.

Ongoing clinical studies are directed at novel mechanisms of action as well as an evaluation of the optimal administration schedules of multimodality therapies and addressing mechanistic questions related to biological activity. Important elements of these studies have included: the collection of complete clinical information on treated patients regarding toxicity and response to treatment; the performance of pharmacokinetic studies of new drugs when appropriate; and the conduct of correlative laboratories studies to further define potential mechanisms of action.

The goal of the Experimental Therapeutics Program is to critically evaluate novel therapies in well designed, hypothesis driven, phase I and phase II studies for a range of human malignancies. The ability to compete successfully for novel chemotherapeutic agents has been greatly enhanced by collaborations with Dr. Leslie Shaw of the Department of Pathology and Laboratory Medicine. Dr. Shaw's laboratory is equipped to perform sophisticated pharmacokinetic studies on serum and bone marrow samples from patients receiving investigational agents. The Cancer Center has been instrumental in establishing this laboratory for oncologically-focused pharmacology studies. The development, clinical testing, and elucidation of the biologic effects of cytokines, growth factors, and differentiating agents have been an additional focus of this program.

Preliminary results from Dr. Gewirtz's laboratory have shown that c-myb antisense oligomers strongly inhibit the in vitro survival and cloning efficiency of leukemic cells with minimal disruption of proliferation of normal hematopoietic cells. C-myb antisense ODN inhibited human melanoma cells in a dose-dependent manner. In addition, the in vivo use of c-myb antisense oligodeoxynucleotides in a SCID mouse model of melanoma and leukemia demonstrated tumor growth inhibition and survival advantage for treated animals. Accordingly, these data suggest that c-myb antisense ODN could play a role in therapy of hematologic and solid tumor malignancies. Based upon these results, a series of phase I clinical studies have been designed to evaluate the toxicity of therapy as well as the biological consequences of down regulating the target gene's expression, at both a clinical level and a fundamental level through linked laboratory studies. With recent approval of an IND for the c-myb antisense (LR-3001) by the FDA, these studies are being initiated. The first application of LR-3001 will be as a bone marrow purging agent in studies directed by Dr. Selina Luger. Future studies will include phase I studies in patients with solid tumors, with a focus on lung cancer and melanoma.

We are currently exploring the myeloprotective effects of Interleukin-1 in patients receiving high dose cyclophosphamide. This NCI CTEP-approved phase I study is designed to evaluate the myeloprotective properties of IL-1 using three different doses and schedules of IL-1. Correlative laboratory studies include flow cytometric analysis of peripheral blood for hematopoietic precursors (CD34+, HLA-DR+) and colony forming assays. Preliminary results demonstrate significant increase in total WBC counts 24 hours after the first dose of IL-1, increased levels of CD-34+ cells after 5 days of IL-1 therapy and no effect of IL-1 treatment on hematopoietic colony formation.

Based upon preclinical and clinical data, a novel topoisomerase 1 inhibitor, topotecan, is undergoing clinical evaluation in patients with refractory lymphoma. Topoisomerase 1 and 2 are nuclear enzymes that play critical roles in relaxing supercoiled DNA. These enzymes have emerged as novel targets of cancer chemotherapy. Ancillary laboratory studies include an assessment of topo 1 levels in pretreatment tumor specimens to correlate antitumor response to topo 1 levels.

We have recently completed a pilot study which evaluated a chemoprevention strategy for patients with atypical nevi (dysplastic nevi), a group at risk for developing malignant melanoma. Dr. Schuchter and Dr. Halpern (Dermatology) have conducted a controlled pilot study of topical tretinoin (trans-retinoic acid) in patients with floridly expressed atypical nevi, there was significant reduction in the clinical atypia (marked fading and/or disappearance) of treated lesions in comparison to untreated lesions. Histologic analysis revealed reduction in cytologic atypia and cellularity in treated lesions. The hypothesis is that reversal of clinical and histologic atypia of these intermediate lesions of tumor progression may lead to melanoma prevention. A follow-up study is planned in which both topical and oral retinoids will be evaluated.

A major focus of this program is the evaluation of new therapies for the treatment of metastatic melanoma. Ongoing studies include phase II study of all trans-retionic acid (ATRA) in patients with metastatic melanoma. This study is based on the hypothesis that the differentiating effects of ATRA can reverse the malignant phenotype of malignant melanoma, resulting in tumor regression. Specific aims are to determine the efficacy and safety of ATRA in patients with metastatic melanoma. Ancillary laboratory studies will determine whether retinoic acid treatment alters expression of retinoic acid receptor and whether the pretreatment expression pattern of retinoic acid receptors predicts clinical and laboratory outcomes. In addition, we are currently evaluating the efficacy of Taxotere in patients with metastatic melanoma This study, sponsored by NCI CTEP, is jointly conducted by the University of Pennsylvania and Albert Einstein Cancer Center in New York. In this study, patients with metastatic melanoma with no prior chemotherapy, are treated with 100 mg/m² of Taxotere, over one hour, every 21 days. Thus far, 13 patients have been treated and the major toxicity has been grade 4 neutropenia. Five patients have had hypersensitivity reactions but were able to continue on therapy with additional dexamethasone and diphenhydramine. Preliminary data suggest that Taxotere is active in melanoma with one complete response and two minor responses.

We are participating in the first randomized clinical trial of DTIC alone versus DTIC, BCNU, Cisplatin, and Tamoxifen in patients with metastatic melanoma. The objective of this Phase III, randomized, prospective clinical trial, conducted by a consortium of institutions (University of Pennsylvania Cancer Center, Memorial Sloan-Kettering, Indiana University) is to determine whether the overall response rate and survival of combination chemotherapy is superior to monotherapy with DTIC. Single institution phase II studies of combination chemotherapy with Tamoxifen biomodulation suggest a 40-50% response rate, but whether this impacts on overall survival is unclear. The results of this clinical study will help to define standard therapy for patients with disseminated melanoma.

Future studies include an evaluation of therapeutic gene therapy vaccines with a focus on the the transduction of B7 (an important co-stimulatory molecule necessary for T cell response) and cytokine genes into autologous breast cancer cells and melanoma cells. For more details see Dr. Guerry's, Dr. Eck's, and Dr. Lee's sections. New agents to be tested include bryostatin 1, CPT-11, and synthetic retinoids, and the chemoprotective effects of Taxol.