Co-leader: David Carbone, MD, PhD
Co-leader: Denis Guttridge, PhD
The Translational Therapeutics Program (TTP) is one of five trans-disciplinary, highly collaborative research programs at the OSUCCC – James. Within this context, it has a history of high-impact science.
The program focuses on solid tumors and continues to grow through strategic recruitment and program development. It includes 58 investigators from 22 academic departments in six of The Ohio State University’s 14 colleges. Multiple members have programmatic grants with inter-program collaborations and training grants.
It is the only center in the country to have both an NCI P01 and SPORE grants in sarcoma.
Key Program Objectives
- Identify genomic and signaling pathway alterations in solid tumors for the development of targeted therapeutics
- Identify targetable tumor-host interactions mediated by macromolecules and extracellular vesicles
- Develop biomarkers in solid tumors for prognosis and selection of therapy
- Develop collaborations that lead to multiple programmatically funded projects in target cancer types
Program Strengths and Attributes
- NCI contracts that support phase I and phase II clinical trials
- The new James Cancer Hospital, the patient-care component of the OSUCCC – James, tightly integrates research and patient care; e.g., wet and dry translational research labs are located on alternating patient floors
- Strong emphasis on cancer genomics research and clinical care, including a Precision Cancer Medicine Clinic
- 21 Shared Resources provide specialized services that support development of novel therapies
- A focus of microRNA expertise
- Translational oncolytic virus research
- The Wright Center of Innovation in Biomedical Imaging at Ohio State—offers animal imaging, microimaging and molecular-agent imaging
- The Drug Development Institute at Ohio State—facilitates the development and licensing of agents that have commercial potential
- Broad opportunities for trans-campus collaboration—The Ohio State University is a land-grant university with 14 colleges located on a single campus, offering rich opportunities for collaboration. OSUCCC – James members come from a range of Ohio State colleges:
- NCI-grant supported natural-products discovery program;
- Computational drug-development expertise
- Public Health
- Veterinary Medicine
- Canine clinical trials program
- Food, Agricultural and Environmental Sciences
- Food processing facilities and Sensory Analysis Lab
- Functional foods expertise
- Arts and Sciences
- Nationwide Children’s Hospital and Battelle Memorial Institute
- Proximity to Ohio Supercomputer Center
- A culture of mentoring—Senior faculty mentor junior faculty to help them obtain their first research grant.
TTP Cancer Focus
- Head and Neck
Early therapeutics development with phase II emphasis (261201100070C)
PI: Miguel Villalona, MD
- Conduct phase II clinical trials of NCI-sponsored agents to evaluate their biologic effects on their molecular targets
- Evaluate other relevant biologic effects
- Determine clinically relevant outcomes and correlates
Network Lead Academic Participating Site for the NCI National Clinical Trials Network (U10 CA180850)
PI: Richard Goldberg, MD; John Byrd, MD; Arnab Chakravarti, MD; David Cohn, MD, Electra Paskett, PhD
- Investigate new therapeutic agents in phase I clinical trials
- Evaluate novel drug combinations and multi-modal therapies
- Design protocols that integrate molecular genetics, biochemistry, pharmacology, immunology and biostatistics
- Maximize targeted therapy efficacy by exploiting tumor heterogeneity
- Improve the management of cancer-related symptoms
- Train the next generation of oncology researchers, physicians, nurses and allied medical personnel
SARC sarcoma SPORE (CA168512)
- Provide the infrastructure for collaboration on translational research for sarcoma
- Determine the biological basis for observations made in individuals with sarcoma
- Develop novel treatments to improve sarcoma outcomes
Studies of childhood sarcoma (P01 CA165995)
PI: Peter Houghton, PhD
- Characterize the interrelationship of three integrated molecular signaling pathways that are active in childhood sarcomas
- Identify combinations of inhibitors that target these pathways and are likely to improve patient outcomes
- Develop novel therapeutic strategies for treating advanced childhood sarcoma
Circumventing barriers to effective oncolytic virotherapy of malignant gliomas (P01 CA163205)
PI: Michael A. Caligiuri, MD
- Investigate the hypothesis that replication and dispersal of an oncolytic herpes simplex virus type 1 (oHSV) in glioblastoma are impeded by multiple viral- and host-based barriers and responses during initial phases of viral infection and replication
- Develop pharmacologic and genetic modalities that circumvent these barriers and responses and increase the efficacy of virotherapy for malignant glioma
Training hematology and oncology fellows in clinical research (T32 CA165998)
PI: Miguel Villalona-Calero, MD; Steven Devine, MD
- Provide a state-of-the-art clinical research training experience for postdoctoral fellows in hematology and oncology with an MD, DO or equivalent degree who have demonstrated a firm commitment to patient-oriented cancer research
- Prepare hematology and oncology fellows in the Divisions of Hematology and of Medical Oncology for academic careers in clinical and translational cancer investigation
- Agents that target altered signaling pathways: MEK1/2 in biliary cancer
- Host-tumor interaction: NK cells in glioblastoma multiforme for oncolytic therapy
- Biomarkers for diagnosis and selection of therapy (miR-based detection of nanoparticle technology, FANCD2, ARAF detection by deep sequencing, and other driver mutations by precision sequencing.)
MEK inhibitor selumetinib shows promise for advanced biliary cancer. A 28-patient, multi-institutional phase II study led by Ohio State examined the use of the kinase inhibitor selumetinib in advanced biliary cancer, a malignancy that lacks effective therapy. One patient showed a complete response, two patients showed partial tumor shrinkage and 17 patients experienced stable disease for up to 16 weeks. Median progression free survival was 3.7 months, and patients taking the drug regained weight and did better clinically. The findings suggest that selumetinib promotes muscle gain in patients with cholangiocarcinoma, and that further investigation is warranted.
PI: Tanios Bekaii-Saab, MD
Published in the Journal of Clinical Oncology
NK cells impede oncolytic viral therapy for glioblastoma using natural cytotoxicity receptors. The findings show that shortly after administration of a therapeutic oncolytic virus, natural killer (NK) cells moved in to eliminate it in the brain. NK cells attacked the viruses when the cells expressed NKp30 and NKp46 cell-surface receptors, causing the NK cells to recognize and destroy the anticancer viruses before the viruses could destroy the tumor. Blocking this immune activity gave the virus more time to kill cancer cells.
Co-senior author: Michael A. Caligiuri, MD
Published in Nature Medicine
Loss of microRNA-122 in liver cells leads to liver cancer. The study, led by OSUCCC – James researchers, found that deleting mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling hepatocellular carcinoma (HCC). The molecular regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. The study showed that delivering miR-122 to a mouse model of HCC strongly inhibited tumor development. The findings suggest that developing a drug that restores microRNA-122 levels might offer a new way to treat for certain HCC patients.
PI: Kalpana Ghoshal, PhD
Published in the Journal of Clinical Investigation with an accompanying commentary
Study identifies role of the muscle microenvironment in cancer-induced wasting. Cancer-induced cachexia, or muscle wasting, damages skeletal muscle. Normally, muscle stem cells (satellite cells) would proliferate and repair such muscle damage. A study led by OSUCCC – James researchers showed, however, that factors released by the tumor blocks muscle stem cells from differentiating into muscle cells, leaving them unable to repair cachectic muscle fibers.
PI: Denis Guttridge, PhD
Published in the Journal of Clinical Investigation
Candidate driver mutation identified in lung-cancer trial “super responder”. A multi-institutional study led by OSUCCC – James researchers describes a patient with advanced adenocarcinoma of the lung who was treated with sorafenib while on a clinical trial. Of 306 patients in the trial, 3 percent responded to sorafenib. One patient had a complete response that last for five years. She had been headed for hospice care when she entered the trial. They engineered the mutation into normal lung cells and showed that this abnormal gene formed tumors, and that the tumors were inhibited by sorafenib. They identified the same mutation in 1 percent of an independent group of lung cancer cases. The findings were an example of a candidate-activating mutation that can be therapeutically targeted.
Senior author: David Carbone, MD, PhD
Published in the Journal of Clinical Investigation
Precision cancer medicine protocol evaluates a mechanism for using tumor sequencing and sequence results in patients with advanced or refractory cancer. The study includes high-depth molecular tumor analysis, and a precision tumor board that recommends patients to clinical trials with molecular eligibility for targeted inhibitors (PI3K, RET, RAF, FGFR and ALK). Data from this study will be used for basic, translational and clinical research.