MESSAGE FROM THE DIRECTOR

Case CCC Annual Scientific Retreat Follow-Up

I would like to follow up on our retreat, held July 8-9, 2011.

From a scientific point of view, it was an outstanding example of the high quality and highly integrated and interactive science that is taking place across our cancer center. We heard from investigators practicing some of our priorities - developing multi-investigator efforts and using transdisciplinary approaches to solve complex scientific questions.

Some examples of the outstanding work presented include:

Direct Measurement of Host Adaptive and Innate Immunity In Vivo
Alex Huang, MD, PhD
Alex described a series of experiments using two-photon technology to analyze the specific interactions between cells in the immune system.  This technique has applications in many areas including inflammatory diseases as well as cancer. In addition, he is collaborating with investigators studying the stem cell niche.

"Eph"ective targeting of metastatic diseases: An old drug with new tricks
Bingcheng Wang, PhD
Bingcheng is evaluating agents, which activate the EphA2 pathway of signal transduction and block tumor cell metastasis. His group is now evaluating the ability of small molecule activators of EphA2 to block Akt phosphorylation.

Targeting PTPmu: Molecular Imaging and Novel Therapies for Glioblastomas
Susann Brady-Kalnay, PhD
Susann showed some wonderful data, using time-lapsed direct tumor imaging, demonstrating that cleaved PTPmu promotes migration. Her laboratory's data suggests that this phosphatase may be an important target for therapeutics in glioma.

Two recent additions to the Cancer Center faculty gave talks on their research programs in breast cancer and brain tumors respectively.

Mechanisms of EMT and metastasis stimulated by TGF-beta
Bill Schiemann, PhD
Bill provided data on the important role that TGF-beta plays in epithelial mesenchymal transition and metastasis. The data included recent gene expression profiling and methods to segregate cells into dormant clustering tumor cell populations versus those that remain independent, migrate, and proliferate.

Motors, Movement, and Malignancy
Steven Rosenfeld, MD, PhD
Steve studied the role of the PDGF pathway in the migration and invasion of glioma and pointed out the critical role of myosin to this process. He again uses time-lapse photography to image this migration process in brain tumors..

In the area of population science, we had two talks that assessed cancer prevention from very different vantage points.

The Prevention Research Center for Healthy Neighborhoods: Current Research and Opportunities for Cancer Prevention
Elaine Borawski, PhD
Elaine pointed out the high degree of disparity that exists within our local Cleveland neighborhoods in tumor incidence and death. This disparity is due in large part to lack of access and utilization of health care facilities, as well as a lack of effort to maintain a healthy lifestyle in a healthy environment or to seek early detection and screening studies in common cancers. Having defined these problems, studies of interventions that would affect a change in these at risk populations remain a priority for our Cancer Center members and our institutions.

Impact of Aging, Energy Balance, Genetics and Inflammation on Gastrointestinal Malignancies
Nathan A. Berger, MD
Nate described very interesting strain-specific and chromosomally delimited mouse models of susceptibility to weight gain and cancer risk that could serve as models for intervention studies for at-risk human populations. Of note was the observation that olive oil did not promote colon polyps, whereas corn oil and coconut oil did, particularly in obesity prone mouse strains.

Two young investigators also provided the approach they are taking in the development of new therapeutics for cancer.

Autophagy as a mechanism of resistance to imatinib mesylate (Gleevec) in the treatment of gastrointestinal stromal tumor
Brian Rubin, MD, PhD
Brian described his studies using the kinase inhibitor, imatinib, in GIST tumors. His group has identified a critical clinical problem by validating that the agent does not kill the tumor cells, but only blocks their proliferation. This work lead to studies that would define the sensitivity to killing of cells that have been blocked but remain in a non-proliferative state, in large part due to protective mechanisms of autophagy.

From black-eyed peas to targeted cancer therapies
Nicole Steinmetz, PhD
Nicole described her very ingenious efforts to package molecules, both molecular and small drugs, into plant viruses for mass production as therapeutic imaging and other targeting agents. These could then augment the armamentarium of delivery platforms using nanotechnology for effective cancer imaging and therapeutics. Studies such as hers will be the focal point in a new initiative the Cancer Center is undertaking with Biomedical Engineering to develop better collaborative interactions between cancer biologists and experts such as Nicole. A collaborative RFA is planned linking biology to nanotechnology and imaging efforts.

On Saturday, we reviewed the clinical research program with presentations by John Sweetenham and Neal Meropol on access and utilization of the infrastructure for clinical trials within our cancer center, and opportunities to conduct Phase III clinical trials through cooperative groups and to have access to their tissue and clinical data repositories to conduct more scientifically based research with concepts developed in Cancer Center member laboratories. Neil, Mitch Machtay, and a number of other cooperative group site leaders can assist any Cancer Center member in developing an initiative application to a cooperative group to gain access to tissue and clinical data repositories. It is a common experience that support from a cooperative group increases the likelihood that a grant will be funded.

The final three presentations provided insight into navigating multi-investigator efforts in the clinical research space.

Clinicopathologic databases
Mikkael Sekeres, MD
Mikkael described his efforts to develop a longitudinal, local database for patients with acute leukemia and myelodysplastic syndrome. This has spawned numerous publications on the demographics and management, as well as important procedural issues related to improving quality in the management of AML and MDS. Mikkael pointed out the collaborative nature of efforts to develop new hypotheses require that the database be a centralized resource, built up with each new investigator.

Pipeline of home grown drugs
Afshin Dowlati, MD
Afshin described the rich resource of drug development taking place within the Cancer Center. In some instances, new drugs have been developed based on long-standing interest in pathways and processes such as ribonucleotide reductase and DNA repair pathways. In other instances, pathways have led to high throughput drug screening with further modification through medicinal chemistry. Some of the drugs described were Methoxyamine, a uracil glycosylated inhibitor, securinine, which promotes AML differentiation, nimesulide a Cox 2 inhibitor, 5-ind a non-natural nucleotide, as well as a series of new efforts supported through the Cincinnati drug discovery collaboration with CWRU.

Technology Commercialization
Neil Veloso, MS, MBA
Neil described the approaches taken at the Cleveland Clinic Innovation Center to promote drug development and the issues and processes involved with licensing, collaborations with pharmaceuticals, and taking advantage of intellectual property to promote clinical investigation, and the common complexities that emerge during collaborative projects.

While most members did not participate in the mentoring session, the graduate students and post docs really appreciated the time Barbara Bedogni, PhD, Youwei Zhang, PhD, Agata Exner, PhD and Kishore Guda, DVM, PhD, David Wald, MD, PhD, Cheryl Thompson, PhD, and Jill Barnholtz-Sloan, PhD spent with the trainees. They each described their own approaches to career development, mentoring, seeking advice writing grants, and in general developing a positive trajectory in cancer research. I really appreciate the time and effort that they took with our trainees.

The scientific program breakout sessions provided time to review the scientific focus area initiatives and strategic plans for each program. This was followed by presentations on Friday and Saturday to the membership about the key strategic initiatives being developed by the program leaders with the support of program membership . This process will culminate in a strategic plan document that will be circulated in August and September for member review, and will include specific initiatives for each scientific program including:

• focus areas for the next five years
• needs in terms of new recruitments that are programmatically aligned and shared resources from emerging technology

As noted in the scientific presentations, many of these initiatives will promote transdisciplinary efforts that cut across our major themes of basic science, clinical, and translational research including prevention and control and the use of new technologies for developing biomarkers and therapies that target critical cancer pathways.

Stan Gerson, MD
Director, Case Comprehensive Cancer Center