The Grace Cancer Drug Center (GCDC) is comprised of 24 major research laboratory units, primarily contained within a six-story structure centrally located on the campus of Roswell Park Cancer Institute. The Center provides a unique facility for basic research and training in the areas of molecular pharmacology and experimental therapeutics as it relates to improving the treatment and management of cancer. With a focus entirely on cancer, the GCDC represents one of the largest academic research facilities of its kind in the United States.

Inherent in the organization, programs and goals of the GCDC is a long-standing emphasis on a multidisciplinary approach to experimental cancer therapeutics. The center houses laboratories in medicinal chemistry, tumor cell biology, morphology, biochemistry, molecular biology, biochemical and molecular pharmacology, immunopharmacology and drug discovery and development. By promoting close and frequent interactions between scientists from a variety of disciplines, the GCDC provides a fertile environment for the identification, validation and exploitation of targets for cancer treatment and control. These interactions are further enriched by the existence of several discrete groups of investigators within the GCDC which focus on specific aspects of target identification, interaction and exploitation. The Drug and Treatment Discovery Group has experts in chemistry, biochemistry, and biochemical and molecular pharmacology who interact in a concerted manner towards the identification of viable therapeutic approaches and strategies in experimental systems, and ultimately, towards their stepwise development towards clinical trial. Another group focuses on cell cycle regulation, apoptosis and signal transduction for the identification of novel targets for cancer treatment and control. A third group provides pre-clinical therapeutic and toxicological testing in developmental phase of agents for target exploitation. The ability to implement advanced research and training programs is further strengthened by well-established clinical liaisons at RPCI and by collaborative interactions with other scientists at RPCI and elsewhere.

The evaluation and therapeutic development of new agents and treatments originated in laboratories within the GCDC or from University, Government and Industrial sources represent a primary activity of the GCDC. Medicinal chemists focus on novel nucleosides as potential nucleic acid-directed antimetabolites or cyclin-dependent kinase inhibitors, and, in other cases, on compounds or oligonucleotides designed to interfere with gene transcription, cellular methylation and on inhibitors of polyamine biosynthesis/function. Recent developments have led to the identification of new polyamine analogs which, on the basis of antitumor activity against human xenografts, are now undergoing Phase I and II clinical trials against melanoma and other solid tumors at several major clinical centers. Other areas which are being investigated include antiangiogenic and antimetastatic agents and differentiation-based treatments as well as innovative approaches for countering drug resistance in tumor cell populations. Subsequent development of promising agents and biologicals derived from internal and external sources includes testing for biological activity in in vitro and in vivo model systems, preclinical pharmacological studies, and complete GLP toxicological evaluation leading to Investigational New Drug status. New human tumor model cell systems have been developed for drug evaluation in vitro and established in athymic nude mice for in vivo studies.

The basis of cancer chemotherapy is predicated on the existence of fundamental genetic, structural, and/or functional differences between normal and malignant tissues. Mechanisms of cell differentiation and maturation in epithelial cells, breast tissues and cells of hematopoietic lineages are being investigated in expectation that they will provide useful and perhaps non-toxic approaches to cancer chemotherapy. Metabolic differences involving polyamines, methylation, purine metabolism and polyglutamylation are also being studied in search of distinctions worthy of therapeutic intervention. Several laboratories are focusing on the therapeutic potential of pathways and proteins involved in the dysfunctional regulation of cell cycle progression in cancer cells and how known and novel small molecule drugs may impact on them. In related studies, the morphologic distribution of protein kinases is being evaluated with respect to various aspects of cell differentiation and growth. Other studies are focussing on regulatory events and particularly those associated with gene expression and its control in the context of the aberrant signal transduction, loss of tumor suppressor activity cell cycle, growth, carcinogenesis, cell differentiation and the potential exploitation of novel apoptosis genes and pathways. The development of molecular technology to specifically alter expression of target genes and to monitor the consequences from both biological and therapeutic perspectives is also currently underway. The identification and cloning of a unique alternative splice variant of the p53 suppressor gene as well as a naturally occurring antisense to thymidylate synthase may have diagnostic as well as therapeutic implications. Intrinsic to the translation of leads emanating from these programs to practical application is the backdrop of chemistry resources, appropriate in vitro, and in vivo test systems, and GLP toxicology all of which are available within the GCDC. (see above)

Emphasis is placed on the acquisition and integration of pharmacological, biochemical and molecular information related to useful chemotherapeutic agents, and on the evaluation of the basis for their selective toxicity. Such interests lead towards the identification of means to further increase the selectivity of drug action against tumors. Target cell determinants of drug action and selectivity are being identified in tumor and normal cells and the interactions between drugs and molecular endpoints are being assessed. The modulation of drug action as a result of the modification of the metabolism of a target cell by an agent not necessarily active per se on tumor cells (metabolic modulation) is an approach which was developed in the GCDC several years ago and continues to be vigorously pursued in the context of new molecular findings as a means to modify selectivity of drug action. The reduction of drug toxicity towards improving its therapeutic index is also being pursued. The demonstration that tumors have antigenic characteristics not present in normal tissues of the adult suggests that immunological responses to these antigens may be exploited therapeutically. The relationships between cancer chemotherapy and immunity constitute another interest. The phamacological, biochemical and molecular bases for the selectivity of anticancer drugs in both target tumors and immunological compartments is being investigated in an attempt to establish therapeutic treatments based upon cooperative interactions between chemotherapy and host immunity. Several groups are examining the basis for clinical resistance to various antitumor agents with relevant focus on P-glycoprotein as well as polyglutamylation in the case of resistance to methotrexate. Molecular studies on the regulation of gene transcription in TATA-less and CATT-less genes may provide another basis for selective drug action. Cell population kinetics are also being investigated as they or tumor cell heterogeneity may affect selectivity of drug action and target cell response to an agent or biological factor.

A major effort is being placed on carrying out an effective translational research program for clinical biochemical and pharmacological studies through increased cooperative research with clinical departments at RPCI and elsewhere. Continuing implementation of this research area is essential to ensure both the possibility of verifying the clinical validity of treatments and approaches developed in the other parts of the GCDC, and the possibility for the GCDC investigators to benefit from the feedback of information and scientific stimulation from the clinics. This research area includes three general groups, namely; (1) those which are related to the study of the mode of action of known and newly developed drugs; (2) those pertaining to the development of new treatments, particularly through the identification of the pharmacological and molecular determinants of tumor sensitivity in individual patients; and (3) those which are concerned with the biochemical, molecular and biological characteristics of different types or stages of cancer as a basis for the design of new treatments.

Several additional functions carried out by individual staff members contribute to the research and educational atmosphere prevailing in the GCDC. Thus, participation in cooperative programs or collaborative studies with members of other departments at RPCI or with colleagues working at other Institutions, represents an important means to achieve broad scientific goals, to exert leadership in the scientific community and to obtain scientific input and stimulation. Participation in peer review or task-oriented committees also represents an opportunity to serve in the scientific community and provides additional interactions and cross-fertilization.