James P. Thomas - US grants

The general goal of the research is to understand and model the perception of visual patterns by normal, human, adult viewers. The proposed experiments investigate how the visual system combines the information provided by the different components of a multicomponent spatial pattern. The individual components are spatial Gabor wavelets which, existing physiological and psychophysical research indicates, are processed separately at early cortical stages. Patterns are formed by spatially and temporally superimposing components which differ enough in the Fourier domain (e.g. 90 deg difference in orientation, 2 octave difference in spatial frequency) to assure separate initial processing. The specific aims are to (1) test and elaborate current models of nonlinear interactions, specifically contrast gain control mechanisms; and (2) define the characteristics of second-order combining networks which combine information from different components in order to represent object features such as textures, edges, and motion. The proposed experiments are psychophysical and the task of the viewer is always to discriminate between two very similar patterns. Discrimination under masking is used to isolate and evaluate nonlinear processes. Combining processes are isolated by holding the number of components constant while varying the number of components which provide cues to discrimination and varying the way in which the cues are combined (configuration effect). The results of the proposed studies will be useful in designing and interpreting physiological studies of post-V1 cortical regions, e.g. V4, and may lead to improved understanding of visual deficits, such as dyslexia, in the perception of multi-component patterns.

DESCRIPTION (Applicant's Description) Colorectal cancer is the second leading cause of cancer death in the United States. There are no curative chemotherapy regimens for metastatic disease. Only two active drugs are available in this disease, illustrating the need for identification and development of new active agents for this malignancy. Perillyl alcohol, an orally administered monoterpene, is presently completing preliminary phase I evaluation at University of Wisconsin. As a class of agents, the monoterpenes are active in several different in vivo and in vitro cancer model systems. They inhibit cellular proliferation, induce differentiation and apoptosis and produce differential gene regulation. Phase I results show that perillyl alcohol can be given at tolerable dose levels on a chronic four times daily schedule. In addition, one patient on the first phase I study has now developed significant regression of metastases from colorectal cancer while receiving perillyl alcohol. Together with preclinical data, this is encouraging for further phase II study of perillyl alcohol in colorectal cancer. The primary goal of this project is to assess the clinical activity of perillyl alcohol in patients with metastatic colorectal cancer. Perillyl alcohol will be administered 4 times daily at an initial dose of 1,200 mg/m2/dose with a possible escalation to 1,600 mg/m2/dose. Measurement of clinical activity will include time to disease progression, disease stabilization and/or response rate and clinical toxicity. Two laboratory correlate Studies will be assessed. Mutations in p53 may confer resistance to perillyl alcohol. Available tumor specimens will be assessed for p53 mutations and correlated, if possible, to drug activity. NQO1 is a gene overexpressed in colorectal cancer that produces an enzyme that metabolizes several drugs, including perillyl alcohol. We will measure serum and tumor NQO1 expression and correlate, if possible, with drug toxicity and efficacy.

The OSUCCC Clinical Trials Office (CTO), ratedOutstanding in the 2004 review, supports the centralized administration of protocol development, implementation and conduct for all clinically active research groups. This shared resource provides the trial administration, protocol tracking and monitoring, data management, regulatory processing and financial supervision necessary for the successful conduct of clinical trials in a methodologically-sound, expedient, and cost-effective manner. The CTO came under the medical leadership of James P. Thomas, M.D., Ph.D. in 2005 and the administrative leadership of Janie Hofacker, R.N., B.S.N., M.S. in 2008. The incorporation of independent research groups into the CTO (1999-2004) combined with the ongoing growth of the clinical enterprise (1999-present) is responsible for the growth of the CTO from 38.5 FTEs at the time of the last CCSG submission to 90 FTEs currently. The growth of the CTO has facilitated a 89% increase in accrual to therapeutic clinical trials from 671 in 2004 to 1265 in the most recent 12-month period, 12/30/2008 - 11/30/2009. Accrual to interventional clinical trials has likewise increased 152% from 939 in 2004 to 2,274 in the same twelve months. In 2007, the CTO restructured the clinical coordinating staff into disease-specific teams to provide dedicated and efficient clinical trials support to clinical investigators specializing in the treatment of defined tumor types. This new structure mirrors the reinvlgorated disease-specific committee structure for clinical research implemented by the OSUCCC in 2004. The acquisition of 7,000 nsf of renovated space in Stariing-Loving Hall adjacent and connected to the James Cancer Hospital in 2005 has permitted the spatial centralization of CTO operations. Management infrastructure was improved with the creation of two new supervisory roles, the Clinical Research Manager (who manages all the coordinators within a disease team) and the Data Manager (who manages the data collection team). The creation of the Regulatory and Business Manager positions within the CTO has led to improved utilization of CTO resources. Also in 2007, web-based support for the management of CTO activities was significantly improved via implementation of the OnCore® commercial clinical trial management (CTMS) software solution from Percipenz (Madison, Wl). The OnCore® system is the most widely adopted CTMS among academic cancer centers across the United States and is actively being integrated with our CaBIG capabilities. This system provides for vastly improved tracking of all clinical research activities and provides CTO staff as well as OSUCCC leadership and membership with the tools to monitor all phases of the process of patient accrual and trial implementation. The CTO interacts with other CCC shared resources including the Biostatistics, Leukemia Tissue Bank, Clinical Trials Unit/Clinical Trials Processing Lab and Biorepository Biospecimen Shared Resources and supports the activities of the Clinical Scientific Review Committee and Data and Safety Monitoring Committee. The training and continuing education of clinical research staff and OSUCCC physicians is a central function of the CTO.

PROJECT SUMMARY An effective National Cancer Clinical Trials (NCTN) must be led by centers with commitment to, and expertise in, the collaborative clinical trials process. The Medical College of Wisconsin (MCW) has a 45-year tradition of such commitment as demonstrated by scientific leadership in development and conduct of clinical trials in association with NRG Oncology, Alliance for Clinical Trials in Oncology, ECOG-ACRIN, and SWOG, in addition to leadership and substantial accrual to other National Cancer Institute (NCI)-funded trials networks. In the past 5 years, the Froedtert & MCW Cancer Center (FMCWCC) has gone through transformative growth and is well- positioned to exert sustained meaningful influence as a Lead Academic Participating Site (LAPS). FMCWCC has a leadership team has diverse experience, a proven track record, and an effective infrastructure that will continue to provide scientific leadership in the development of trials, contribute to timely accrual and completion of trials, and mentor the next generation of investigators. FMCWCC will support the mission and the operation of the NCTN by 1) providing leadership in developing important and successful multicenter trials that address critical issues in cancer diagnosis and treatment utilizing MCW expertise in pre-clinical, translational, and early phase and advanced phase clinical research; 2) providing robust accrual to NCTN trials with wide participation by all MCW cancer disciplines; 3) Developing the next generation of NCTN clinical scientists through mentoring programs and advanced methods training. MCW has played a scientific leadership role in national adult clinical trials programs for many decades and has made substantial recent investments in recruitment and infrastructure to vigorously grow its clinical trial program. This comes with an explicit commitment to grow NCTN activities by: (i) empowering the NCTN leadership in our Cancer Center infrastructure; (ii) engaging faculty with extensive expertise in both the cooperative groups and other non-profit trials networks to develop, activate and accrue to NCTN trials; (iii) centralizing and expanding clinical research support activities to further increase capacity, efficiency and accrual; and (iv) mentoring the next generation of investigators.