Randy Burd, PhD Core Director Thomas Jefferson University 111 South 11th Street Philadelphia, PA 19107-5097

Adam P. Dicker, MD, PhD Core-Co-Director Thomas Jefferson University 111 South 11th Street Philadelphia, PA 19107-5097

Background and Significance of Proposed Work

Half of all cancer patients will receive radiation therapy during their course of treatment for cancer. Nearly 500,000 patients in the United States were treated with radiation in 1990, (1) establishing radiation therapy one of the most widely used treatments for cancer.

Radiation therapy is a definitive and effective modality for the treatment of a number of tumors, however there still remains a need to need to improve the cure rate. One approach is to use a “radiosensitizer”, a drug or biologic modifier that will sensitize cells to radiation in conjunction with radiation therapy. This has traditionally been through the combined use of chemotherapy and radiation therapy. The nature by which drugs and radiation may interact has been divided by Steel (2;3) into four groups: 1) spatial interaction; 2) toxicity independence; 3) protection of normal tissue and 4) enhancement of tumor response.

Combined Modality Treatment and Limitations of Current Cancer Therapy.

The integration of chemotherapy and radiation therapy either sequentially or concomitantly, is having a greater role in the treatment of cancer. The optimal usage of chemotherapeutic agents and/or radiation requires predictability of the cell-cycle for optimal sequencing of drug/radiation treatment. Unfortunately, tumors are inherently unstable exhibiting gene amplification and undergo frequent genetic alterations. In addition, mutations and deletions of the p53 tumor suppressor gene in cell lines are associated with resistance to a variety of DNA-damaging agents (4-6) and may be responsible for drug and radiation-resistance seen in the clinic and thus, lack of cooperation between the two modalities.

Over the past few decades, there has been considerable interest in developing new agents to improve the outcome for patients with solid tumors. However, traditional cytotoxic therapies are nonspecific and do not discriminate between tumor and host cells (7). Furthermore, as they are generally effective against rapidly dividing neoplasms (8), their efficacy against solid tumors is limited. Even where cytotoxic agents are effective, tumor resistance may develop (9). The lack of specificity and limited efficacy of traditional cytotoxic agents has led to the rational design and development of targeted therapies that aim to differentiate between malignant and nonmalignant cells, thereby producing a higher therapeutic index and less toxicity than conventional therapies (7) (Figure, this page). In order to develop such agents, it is necessary to identify the aberrant biochemical and molecular pathways that distinguish malignant cells from nonmalignant cell (10). As with nonmalignant cells, tumor growth and progression depend largely on the activity of cell membrane receptors that control the intracellular signal transduction pathways regulating cell proliferation and apoptosis, angiogenesis, adhesion, and motility (11).

The opportunity to combine inhibitors of specific targets such as; inhibitors of angiogenesis (VEGF Traps (12;13)), epidermal growth factor receptor (inhibitor-Iressa (14-16)) or proto-oncogenes i.e. c-Kit (inhibitor-Gleevec/STI-571 (17;18)) with radiation therapy represents powerful and novel approaches to combined modality treatment with the goal greater tumor local control and possibly a reduction on total radiation dose with attendant reduction of side effects in surrounding normal tissues.

A model for targeted therapy radiosensitization. Cells are less sensitive to radiation under hypoxic conditions than under normal conditions. Approximately 2-3X more radiation is needed to kill hypoxic cells than well-oxygenated cells. Targeted therapeutic may represent a clinically effective radiation sensitizer for hypoxic cells. Our model of cooperative interaction between angiogenesis inhibitors and radiation therapy is presented (Figure, right).

The New Drug Development Program Core (NDDPC) for the RTOG

No US cooperative group has a core facility to pursue critical preclinical studies. The rational design of clinical trials combining molecular targets of cancer cells with radiation critically depends upon a better understanding of the mechanisms underlying radiosensitization. We propose therefore the creation of new entity entitled, New Drug Development Program Core (NDDPC) (Figure-below) that will work with institutions in the Commonwealth. The studies proposed here have the opportunity to be carried out with close cooperation of the RTOG, which has significant experience in clinical trials and an established patient base. This will help ensure the smooth and rapid translation of laboratory and preclinical findings into clinical protocols and subsequently into established clinical therapy. The proposed NDDPC represents a unique opportunity to combine the strengths of a number of investigators focused on targeted therapies in an organization that has depth in experimental radiation oncology and clinical trial design/implementation. This will result in new opportunities pharmaceutical/biotech industry, academic institutions and the citizens of the Commonwealth.

Advisory Board

We will also propose having an advisory board. This board will be composed of patient advocate, survivorship representatives, scientific advisors and representative from large pharma and biotech companies located in the Commonwealth. It will be one of many means to evaluate the performance of the NDDPC.

Develop experimental model systems that faithfully recapitulate the complex biology of human cancer.

To pursue these priorities in vitro, ex vivo, and animal models that faithfully recapitulate the complex biology of invasive human cancer and its precursors are necessary for the discovery and development of novel targeted therapeutic strategies with a high probability of success in treating cancer. Existing animal models have been passaged numerous times reducing their ability to faithfully recapitulate the true characteristics of the original tumor.

Tumor models that recapitulate patient disease are needed to validate that a specific therapeutic agent is capable of affecting its target and to assess the impact of that intervention on tumor growth and metastasis. These models are also required to study signal transduction pathways and gene expression, to test early detection and diagnostic methods, and to develop novel diagnostic and therapeutic strategies. Clinically relevant models will enable investigators to evaluate the role of key genetic alterations in the development of precursor lesions, tumorigenesis, maintenance, invasion, and metastasis. Such studies will also be performed to be in conjunction with the pre-existing NCI Mouse Models of Human Cancer Consortium. It will be essential to apply the compendium of gene expression patterns and genome-wide genotypes of carcinoma described above to the study of these new mouse models and, in turn, to use the models to expand the base of knowledge concerning relevant genotypes and gene expression patterns in human cancer.

Facilitate the discovery and development of targeted therapeutics.

It is likely that specific signaling pathways within tumor cells and between tumor cells, stroma (fibroblasts and endothelium), and the immune system are altered in tumor cells and that once identified, these pathways can be targeted for therapeutic benefit. With this information, it should be possible to identify specific protein targets that are critical to pancreatic cancer growth, metastasis, drug and radiation resistance and design pharmacologic strategies to interact with these critical pathways.

Growing knowledge of the molecular biology of cancer should be used to identify both existing agents that target biologic pathways already known to be critical to cancer tumorigenesis and those that can be identified from new insights into key signaling pathways. It also is likely that substantial benefit can be gained by enhancing standard cytotoxic therapy with new-targeted therapeutics.

IV. INVESTIGATORS

Randy Burd, Ph.D., Director. Dr. Burd received his Ph.D. in Molecular and Cellular Biophysics from the Roswell Park Cancer Inst., where he specialized in radiobiology and experimental therapeutics. Dr. Burd was trained in the laboratory of Dr. Elizabeth Repasky, who pioneered a technique for growing breast tumor models in the gondal fat pad of SCID mice (19) derived from fresh patient surgical specimens at Roswell Park Cancer Institute. He now directs an experimental tumor program at Thomas Jefferson Univ. and maintains several human tumor xenografts in SCID and Nude mice. Dr. Burd also has extensive experience in the design and analysis of experiments evaluating the effectiveness of experimental therapeutics on tumor growth.

Adam Dicker, MD, Ph.D., Co-Director. Dr. Dicker is a board certified radiation oncologist who received his Ph.D. with Dr. Joseph Bertino and his clinical training at Cornell Univ. and Memorial Sloan-Kettering Cancer Center. Dr. Dicker is Associate Professor, Director of Clinical Research and Director of Experimental Radiation Oncology in the Dept. of Radiation Oncology at Thomas Jefferson Univ. Dr. Dicker has direct supervision over a number of research programs at Thomas Jefferson University that integrate molecular therapeutics with conventional cancer therapies both on the preclinical and clinical level. Dr. Dicker is also a member of numerous disease site steering committees (brain, gynecological, and translational) of the RTOG.

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