Hem Onc Research Developmental Therapeutics and Translational Research
Faculty members within the Division of Hematology and Oncology are heavily involved in identification of novel therapies for advanced tumors as well the discovery of novel prognostic and predictive biomarkers. Many of these efforts are outlined in other Research Theme descriptions (e.g. Hematology, Genetics and Genomics, Hematologic Malignancies, Health Services).
The Phase I Program is an important highlight of the Cancer Center and Division. On average 15-20 phase I trials are active at any given time with annual accrual of 70-80 patients. This program is lead by Dr. Afshin Dowlati who is principal investigator of an NCI Phase I grant for early therapeutics development. The program emphasizes collaboration with the NCI, the development of “in-house” agents (such as methoxyamine) and pharmaceutical collaboration. Our disease-specific faculty actively participate and lead Phase I trials (e.g. Drs. Eads, Hoimes, Krishnamurthi,Sharma). In addition, we are a subcontract site for an NCI N01 contract to support phase II investigation with CTEP agents (Meropol subcontract PI; M. Villalona, OSU PI). The Case Comprehensive Cancer Cetner is one of only 7 centers nationally to hold both U01 and N01 cancer drug development grants from CTEP.
The Breast Cancer Program (Drs. Harris, Baar, Owusu [see Health Services section], Silverman) has an active clinical trials program with 9 investigator-initiated, 4 Industry-sponsored and 11 Cooperative group trials either open or going through the regulatory process. Two investigator initiated trials were written and are in the process of activation “Next Generation Sequencing to Evaluate Breast Cancer Subtypes and Genomic Predictors of Response to Therapy in the Preoperative Setting for Stage II-III Breast Cancer” by Harris and “Denditic cell vaccine therapy against stromal peptides in breast cancer” by Baar (recently awarded a Komen Foundation grant for this research). Dr. Baar’s program encompasses the development of investigator-initiated trials in breast cancer vaccines. He has undertaken a clinical trial of MUC-1 peptide vaccination in patients who have completed treatment for early-stage triple-negative breast cancer (BC) (CASE 16107). His Komen award will support a prospective clinical trial of an autologous dendritic cell-based vaccine intended to generate T cell cytotoxic immunity against tumor blood vessel associated antigens..Two of the Breast Program members sit on the ECOG breast committee (Silverman, Harris) and are the designated PI’s for two Intergroup studies (NSABP – B47 and B43).
The Breast Program membership includes a multidisciplinary team of specialist and allied professionals. Many have active research studies ongoing - Plecha (tomosynthesis, breast PET-MRI), Lyons (radiation dose delivery, re-irradiation), Baar (immunotherapy, notch inhibitors), Shenk (high risk clinic, preoperative therapy), Silverman (U/S guided node biopsy, cardiac risk, survivorship, CNS metastases). In addition, a number of members of other departments are actively involved in breast cancer research projects Keri – (breast cancer signaling pathways, novel therapeutics), Schiemann (metastasis, TGFb signaling), Thompson (breast density, miRNAs), Gilmore (preop therapy/genomics, primagrafts, CNS metastases), Jackson (normal mammary biologic, stem cells, stromal-epthelial interactions), Narla (novel therapeutics, genetic susceptibility) DeFeo (ovarian-TNBC studies). Several resources have been developed to facilitate translational research within the program, including primagrafts from breast cancer samples, and several annotated tissue cohorts. These include a cohort of CNS metastases and matched primary samples with a tissue microarray and nucleic acid extraction for gene expression and mutation profiling. In addition, infrastructure is being developed to database all new patients with collection of biospecimens and clinical data. The activities of this group will form the basis for the new developing Breast Cancer Program in the Case Comprehensive Cancer Center.
The Harris lab is a translational laboratory with a focus on cancer genomics and novel therapeutics. We are actively involved in the application of Next Generation Sequencing to biospecimens in the context of clinical trials. The lab will continue to analyze genetic signatures in vivo (from tumor specimens) and ex vivo (tumor mammosphere cultures) to understand mechanism of action of commonly used drugs in breast cancer (trastuzumab, bevacizumab, taxanes) and develop predictive signatures/mutational profiles for therapy selection.
The Gastrointestinal Cancer Program (Drs. Chee, Eads. Krishnamurthi, Gibbons, Meropol, Nock, Saltzman) has an active clinical trials portfolio, including NCI and industry-sponsored research. Dr. Cheng Chee is pursuing therapeutic development with an emphasis on radiographic biomarkers. She has received NCI approval for her study, “ECOG 1213 A Phase I/II Randomized, Double-Blind, Placebo-Controlled Study of nab-Paclitaxel/Gemcitabine plus Wee1 inhibitor vs. Placebo in Treatment-Naïve Metastatic Adenocarcinoma of the Pancreas.” This trial contains a substudy to measure the effect of gemcitabine on vascular flare with FLT-PET. In collaboration with the Case Cancer Imaging Program, Dr Chee is Co-Principal Investigator of 2 studies: 1) A Pilot Study of FLT-PET/MRI in Early Response Monitoring of Anti-Angiogenic Cancer Treatment and 2) A Pilot Study of FDG-PET/MRI in Early Response Monitoring of Pancreatic Cancer Treatment. As described in the Genetics section above, Dr. Chee is also developing methylated vementin as a serologic biomarker in colon cancer. Dr. Jennifer Eads was recently recruited to the faculty as a K12 Scholar, focused on early phase clinical investigation in gastrointestinal cancers. She is PI of a phase I trial of methoxyamine (a base excision repair inhibitor) in combination with temozolamide, with a view towards developing this comination for patients with neuroendocrine tumors. Through the NCI GI Steering Committee Neuroendocrine Task Force, she is also developing a treatment study for patients with poorly differentiated neuroendocrine tumors. Dr. Smitha Krishnamurthi’s research interests are in phase I/II studies and treatment of gastrointestinal cancers. She was the Principal Investigator (PI) for our site for NKTR1Y10, a phase I study of pegylated irinotecan in combination with infusional 5-fluorouracil for patients with advanced solid tumors, which closed to accrual in September of 2012. She will be the site PI of NKTR1Y13 (IRB-approved April of 2013), which will evaluate the effect of pegylated irinotecan on the QT interval. She is the lead investigator for CASE 9209, a National Cancer Institute-sponsored study of FOLFOX chemotherapy plus the novel agent cediranib for advanced biliary cancers (closed to accrual in January of 2013). Funded by the Case Specialized Program in Research Excellence (SPORE) in Gastrointestinal Cancers grant, Dr. Krishnamurthi is evaluating the effect of vitamin D on the expression of 15-prostaglandin dehydrogenase in malignant and normal colorectal mucosa. Dr. Krishanmurthi and Dr. Rami Manochakian are leading a phase II trial of vitamin D in conjunction with chemotherapy in patients with advanced pancreas cancer. Dr. Meropol leads the national trial ECOG 4203 (recently completed accrual), which tests the hypothesis that thymidylate synthase expression confers resistance to 5-flurorouracil. This is the first national trial in patients with metastatic colorectal cancer that assigns treatment based on a molecular classifier. Dr. Meropol also helps to guide the development of national studies through his role as Chair of the NCI GI Steering Committee.
Dr. Matthew Cooney leads the the genitourinary research program team which is focusing on targeted therapeutics for the treatment of advanced prostate cancer and the development of alpha-methylacyl-CoA racemase (AMACR) as a non-invasive diagnostic biomarker. With the collaboration of investigators in the basic science programs they have developed a novel, inexpensive, and portable biosensor to detect prostate cancer without the need for a biopsy. By measuring the AMACR levels in one drop of plasma this biosensor may diagnose cancer and predict aggressiveness of disease. Dr. Christopher Hoimes is a new recruit to the GU malignancy clinical and research programs and is a member of the Phase I oncology team. With an interest in cancer immunotherapy, he will be the PI for an anti-PDL-1 antibody trial and additionally will be the Seidman PI for Case 1Y13 assessing genomics procurement and actionable treatment paradigms for hematologic and solid tumor malignancies. His research program will be focused on developing nanodelivery platforms for bladder cancer.
Dr. Michael Gibson was recently recruited as Medical Director of our Head and Neck Cancer Disease Team. Dr. Gibson’s research focuses on developmental therapeutics with the goal of translating novel drug treatments to the clinic. In the setting of advanced, recurrent/metastatic cancers of the head and neck (thyroid, salivary, nasopharyngeal, squamous cell carcinomas), he plans to work with the translational CORE and head and neck tumor bank to identify targets of sensitivity and resistance—utilizing current technologies such as genome analysis, mRNA arrays, and tissue arrays to analyze protein expression and phosphorylation and epigenetics. Phase I/II trials of targeted therapy will be designed such that serial biopsies may be obtained. Concurrent with the primary aim of response and survival, these biopsies will be analyzed for mechanisms of resistance to the therapeutic agents. Some targets of interest (new and ongoing) include: HER family, PDL-1, src family kinases, and angiogenesis.
The Thoracic Program (Drs. Dowlati and Sharma) in the Division of Hematology and Oncology has been successful in conducting important investigator initiated trials such as CASE 2507 which aims to determine the worth of continuing EGFR inhibition in addition to chemotherapy after progression on EGFR inhibition in patients with EGFR mutations. It also has recently conducted a number of physician investigator initiated trials in Small Cell Lung Cancer with agents such as rebeccamycin and sorafenib. In collaboration with the laboratory of Dr. George Stark at Cleveland Clinic, Drs Sharma and Dowlati are investigating the role of NFkappaB inhibition in overcoming the resistance to EGFR inhibitors in lung cancer. Based on the pre-clinical data from this lab, Dr. Sharma has designed a phase I/II trial of quinacrine and erlotinib in patients with non-small cell lung cancer. He is also supported by an NIH Case CTSA award to conduct microarray gene expression analyses to identify pharmacodynamic marker sof erlotinib and quinacrine in non-small cell lung cancer (NSCLC) cell lines. In collaboration with the Goutham Narla lab, Dr. Sharma is evaluating a new class of drugs which can inhibit the MAPK and AKT signaling together by activating protein tyrosine phophatases (PP2A). As a component of this work leading to a clinical trial, they are exploring the expression of PP2A in lung cancer in relation to other molecular abnormalities.
Dr. Henry Koon is a member of the ECOG melanoma committee and the Cytokine Working Group. He leads a number of early and late phase trials of immune checkpoint inhibitors. His research focuses on biomarkers and patient selection for immunotherapies in melanoma. In collaboration with members of the Genetics Department he is investigating mitochondrial heteroplasmy as a biomarker in melanoma. In collaboration with members of the Pediatric Hematology/Oncology he is investigating the utility of CDK inhibitors in the treatment of melanoma
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