Razelle Kurzrock - US grants

CML patients treated with interferon or bone marrow transplant can enter long-term cytogenetic remissions. Surprisingly, only a portion of these patients will eventually relapse. Because CML patients carry a cancer- specific marker--the t(9;22) resulting in an aberrant BCR-ABL gene and protein--the detection of very low levels of minimal residual disease is now possible with the use of FISH and PCR-based technologies. However, the clinical relevance of minimal residual disease is unclear because of the heterogeneity of outcome in these patients. For instance, bone marrow transplant recipients and interferon-treated patients may show evidence of residual BCR-ABL- positive cells or eve of cytogenetic positivity without clinical relapse. Conversely, we have also observed a PCR-negative CML patient who relapsed within several months. We therefore propose to undertake a systematic analysis of CML patients in cytogenetic remission after treatment with the transplant, interferon, or chemotherapy programs (outlined in this P01) to determine (i) if low levels of residual disease detected by PCR or FISH in bone marrow are accounted for by the presence of BCR-ABL message in cells capable of dividing and forming colonies; (ii) if the study of the percentage of PCR-positive colonies adds relevance to the PCR assay and can help determine which patients with minimal residual disease will relapse; and (iii) if differential expression of the BCR-ABL message and p210/BCR-ABL in hematopoietic cells at different stages of maturation (obtained by cell separation techniques and by stage-specific colony assays) exists. These experiments will be performed in various categories of patients such as those after allograft who are PCR-positive or FISH-positive and relapse as opposed to those who do not relapse. Our results will be compared to those obtained from experiments with interphase vs metaphase FISH in an attempt to understand the clinically different subsets of patients with minimal residual disease and to elucidate the mechanisms by which small numbers of Ph+ cells remain without the occurrence of relapse.

DESCRIPTION (Provided by applicant): Patients with myelodysplastic syndrome (MDS) suffer from, and often succumb to, serious infections or bleeding because of severe pancytopenia, with or without progression to acute leukemia. Current therapy for MDS does not yield a survival advantage, and no form of therapy has proven advantageous enough to warrant being considered standard. Mutated RAS genes are found in about 20 percent-30 percent of patients with MDS. Furthermore, in patients without RAS mutations, Ras may still be activated indirectly because of the effects of other genetic aberrations. It is now known that in order for even mutated Ras to be active, it must move from the cytoplasm to the plasma membrane, a process in which the addition of a farnesyl group by the farnesyltransferase enzyme (FTase) plays an important role. Recently, novel compounds which act as FTase inhibitors and hence interfere with Ras activation have been developed. The goal of this project will be to perform the first clinical study of a novel FTase inhibitor (R115777) in MDS patients and to ascertain the optimum dose for biologic and clinical response. (R115777 is available from the Cancer Therapy and Evaluation Program of the National Cancer Institute.) Our hypothesis is that the patients most likely to respond are those who have baseline Ras activation which can be downregulated after treatment with an FTase inhibitor. We will start with a Phase I dose-finding study. The objective of the initial trial will be to ascertain patient tolerance to R115777, and to estimate optimum biologic dose. These trials will then be expanded to determine subsets of patients who are most likely to show biologic and clinical response. The optimum dose and subsets of patients with biologic response to R115777 will be ascertained by measuring the relationship between administered dose and plasma concentration of R115777 and effects on biologic endpoints: FTase activity, Ras and lamin B farnesylation, and downstream effectors of Ras (MAP kinase and IL-1 (the latter based on our recent results demonstrating that Ras activation leads to autocrine IL-1 production in leukemia)). In summary, this work will determine a dose of R115777 which is both tolerable and maximizes the impact of this molecule on the FTase/Ras system. This dose will then be used to determine if R115777 is effective in the treatment of MDS and if certain molecular/biologic markers are predictive of response. These studies will also enhance our understanding of the relationship between inhibition of farnesylation, effects on downstream effectors, and antitumor activity in MDS, and should be useful as a paradigm for the clinical application of other FTase inhibitors.

[unreadable] DESCRIPTION (provided by applicant): For many malignancies, the molecular aberrations that occur predominantly in cancer cells have been elucidated. Considerable interest has been generated by the discovery of agents which specifically target these aberrations, and several of these compounds have entered into clinical evaluation and are showing great promise. Many of these novel targeted agents behave in ways that are fundamentally different from cytotoxic chemotherapy. For example, new agents may be cytostatic in nature, rather than cytotoxic, or may require long-term administration. These differences call for modifications in the design of clinical trials. Indeed, in contrast to the standard paradigm for Phase I development of classic chemotherapeutic agents based predominantly on determination of maximum tolerated dose (MTD), surrogate markers and functional endpoints may be fundamental parameters for development of targeted agents. We therefore hypothesize that integration of intermediate biologic endpoints which reflect interaction with or functional impact on the target, will provide critical information for determining the optimal biologic dose (OBD) for subsequent Phase II studies. Evaluation of the ability of targeted drugs to modulate, interact with, or inhibit specific molecular and biochemical targets requires effective cooperation between clinical and laboratory investigators. In a large institution such as The University of Texas M.D. Anderson Cancer Center, a strong emphasis on clinical and translational drug development exists. Investigators across the institution have access to all of the many components critical to this endeavor, including analytic chemistry, clinical pharmacology, functional imaging, biostatistics, and numerous basic research laboratories with state-of-the-art expertise in evaluating interactions of the test agents with specific cellular and molecular endpoints and effects on tumor cell growth and apoptosis. This extensive infrastructure for clinical and translational studies will allow us to safely and efficiently evaluate clinical activity and toxicity, pharmacokinetic parameters and pharmacodynamic relationships, and develop clinically-relevant correlates and surrogate endpoints for novel targeted agents given alone or in combination, hence permitting rapid advance of these compounds through early clinical studies. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Pancreatic cancer is an almost uniformly fatal illness, which is notoriously resistant to conventional chemotherapy. Indeed, the only chemotherapeutic agent approved by the FDA for use in this tumor -- gemcitabine -- has a response rate of approximately 5%, underscoring the need for innovative new approaches. Curcumin (diferuloyl methane) is a plant-derived compound that has been used extensively as a dietary ingredient. In vitro and animal model studies suggest that this compound has significant antitumor and chemotpreventive activity. In addition, pharmacologic doses of curcumin have been administered to patients in the phase I setting without significant side effects. Recently, we have demonstrated that curcumin has potent antiproliferative effects against all of five pancreatic cancer cell lines, with the 50% inhibitory concentration (IC/50) being < 5 mu/M in three of these lines. The antiproliferative effects were irreversible, and substantial apoptosis was noted. Of interest, NF-KappaB, which is constitutively active in pancreatic cancer cell lines, was downregulated after curcumin exposure. Levels of effectors including COX-2 and IL-8 were also decreased. On the basis of these results, we propose to do an exploratory clinical/translational trial of curcumin in patients with pancreatic cancer. Our primary objectives will include clinical goals such as determining the tolerance to, as well as response to, curcumin in patients with advanced pancreatic cancer. In addition, the biologic effect of curcumin on both tumor cells and peripheral blood mononuclear cells (the latter being used as a surrogate marker) will be assessed. In particular, the impact of curcumin on NF-KappaB activation, COX-2 and prostaglandin E2 levels, specific cytokine expression, and apoptosis will be evaluated. These studies should provide the foundation for the development of curcumin as an anticancer agent and may lead to a novel approach to the management of pancreatic cancer.

DESCRIPTION (provided by applicant): With the paucity of effective new approaches for early diagnosis, prevention and treatment of cancer, it is anticipated that patient-oriented cancer research, a research discipline in which highly-trained professionals conduct research that directly involves patients or high-risk individuals, will lead to the next significant advances in the cancer field. Indeed, there is increasing recognition that the highly-trained patient-oriented cancer research scientist is essential to the translational process; i.e., application of the enormous knowledge obtained in the basic science laboratory to the clinic. Also important is the scientific, hypothesis-driven investigation of disease in the patient that leads directly to discoveries in the biology, pathophysiology and natural history of cancer in man. Perhaps most significant is the identification of innovative strategies for treatment and subsequent prevention of human disease which can be developed by those highly-trained patient-oriented research scientists. It is clear that this research discipline requires a specialized, more thorough education which encompasses molecular and cellular biology, pharmacology, clinical trial design, and biostatistics, as applied specifically to cancer, a devastating disease of tremendous heterogeneity and complexity. But such an educational program is not common and, therefore, the discipline of patient-oriented cancer research is under-represented at present. Recognizing the importance of this next generation of cancer researchers, it is the purpose of the University of Texas M.D. Anderson Cancer Center Curriculum for Patient-Oriented Clinical Cancer Research Program to develop an effective training program that leads to highly-trained cancer researchers who will effectively bridge the gap between the laboratory bench and the patient bedside. This training program will provide a two-year series of state-of-the-art, relevant didactic lectures focused on oncology, mentored research experiences, and mentored programs for preparing grants, manuscripts, and protocols. Participation in the program will be open to residents, fellows, faculty, and graduate students whose career goals are oriented towards achievement in academic patient-oriented cancer research. Graduates of the program will have received the training necessary to conduct hypothesis-driven cancer research, disseminate the results of this research to the cancer community through publication in peer-reviewed journals and public presentations, and obtain peer-reviewed funding to support their work. These are indeed the hallmarks of the successful academic researcher who will make the next major advances in diagnosis, prevention and treatment of cancer.

DESCRIPTION (provided by applicant): Although knowledge of cancer biology in the laboratory has increased exponentially in recent years, progress in cancer treatment in the clinic has been more gradual. To accelerate progress in the clinic, a larger number of outstanding clinician-investigators is needed to perform patient-oriented, therapeutic translational research. The M. D. Anderson (MDACC) K12 Paul Calabresi Program in Clinical Oncology has taken advantage of an extraordinary environment for clinical and translational research to begin to fill this need. MDACC brings together 1,469 faculty and 29,500 new patients each year with a well-developed infrastructure for clinical and laboratory research and novel ideas that are supported by 254 NCI grants. For 6 decades, MDACC investigators have made important contributions to clinical cancer research. Since the inception of the MDACC K12 Program in 2000, 9 junior-faculty investigators have been trained in patient- based translational research with the program's support. Currently four faculty investigators and two fellows are being trained in this program. All nine of our graduates have become highly productive clinician- scientists, who have published 388 peer-reviewed papers, competed successfully for $10.9 M in grants and contracts and have headed 89 therapeutic protocols. The four faculty and two fellow trainees supported by this award will conduct hypothesis driven clinical trials, participate in a cancer-oriented K30 curriculum and can earn an M.S./Ph.D. in Patient-Based Biological Research. To maximize use of MDACC's extensive resources for clinical, translational and basic research, this combined K12 program will include fellows and junior faculty not only from MDACC but also from the Baylor College of Medicine. This program emphasizes individualized training plans that include didactic classes, clinical trials, laboratory research projects, publication of results, individualized training experiences, and long-range planning. Each Calabresi scholar is guided by a clinical mentor and a translational mentor as well as by the PI and the program's Advisory Committee, composed of experts in clinical, laboratory, and translational research.

Clinical Trials Office The MCC Clinical Trials Office (CTO) provides a full range of research services for all aspects of clinical trials in the Research Programs of the Center. This includes protocol development and preparation, regulatory compliance, quality assurance, data and safety monitoring, research nursing, and study management. It is organized into three divisions, reporting the CTO director, Joanne Mortimer, MD: Study Design and Development, Operations (including Regulatory Affairs, Study Administration and Study. Operations) and Community and Affiliations Liaison. The CTO addresses the needs of clinician scientists in the development and activation of protocols and also functions as an integral part of the health care team in providing state of the art and efficient clinical care to the protocol patient. The CTO has undergone considerable reorganization during the past grant period, with increasing improvement in data quality and accrual to therapeutic trials. As a result of changes, the time required for 1KB approval and contracting has decreased significantly and the quality of data capture has improved. Such improvements have contributed to an increase in patient accruals.

CLINICAL PROTOCOL & DATA MANAGEMENT ABSTRACT The Moores Cancer Center (MCC) Clinical Trials Office (CTO) provides a centralized resource for the conduct of cancer-related clinical research at University of California San Diego (UCSD) including the affiliated Rady Children?s Hospital. The purpose of the CTO is to provide an effective and efficient infrastructure to support MCC investigators in developing, implementing, and reporting on all cancer clinical research studies at MCC. The Moores Cancer Center Clinical Trials Office provides the following services: · Serves as a central clinical research information repository that facilitates Center-wide communications, subject accrual tracking, and monitoring of the progression for all clinical studies from inception to final publication. · Assists MCC investigators in the timely activation and administration of clinical studies, including the preparations and communications required for scientific, ethical, financial, and operational reviews as well as ongoing support for annual regulatory reviews. · Assists clinicians in screening and enrolling patients for clinical research studies. · Coordinates and ensures the completion of patient-specific study requirements. · Provides data management support for clinical research studies. · Prepares medical and research records for internal and external quality and compliance audits. · Provides clinical research training and education to CTO staff and investigators related to best practices in conducting clinical research. · Performs quality assurance activities and monitors compliance with federal requirements such as study registration to clinicaltrials.gov and NCI?s Clinical Trials Reporting Program. · Communicates the availability of clinical studies to MCC physicians, referring physicians, and the public.