With a focus on strong scientific and clinical activity, the ET has successfully competed for an N01 Phase II contract with NCI, a new Program Project Grant (P01) on epigenetics and the OSUCCC–James' first SPORE (P50) grant.
Major accomplishments include:
Phase I (U01) – Michael Grever, MD
Phase II (N01) – Miguel Villalona, MD
P01 Epigenetic Therapeutics – Samson Jacob, PhD
P01 CLL Research Consortium – Michael Grever, PhD
LLS-Center of Excellence in CLL – John Byrd, MD
SPORE in Therapeutics of Leukemia – John Byrd, MD, Guido Marcucci, MD, Clara Bloomfield, MD
V Foundation/AACR Translational Award – Miguel Villalona, MD
NIH-Faculty Training Grant in Therapeutics – John Byrd, MD
Selected Findings & Developments
miRNA 221/222 Confers Tamoxifen Resistance in Breast Cancer
miRNA 155 Dysregulated Early in Hepatocellular Carcinogenesis Development
Epigenetic Silencing of Tumor Suppressor Genes and Mutations in DAPK1 Contributes to CLL
Novel Class of Quinoline-Based DNA Hypomethylating Agents Under Investigation: Will be Developed for Clinical Studies in Man
Explorating Silvestrol as Selective Inhibitor Translation Mcl-1
Developing Epigenetic Therapeutic Approach to AML in the Elderly
Developing Effective New Therapeutic Agents for Drug Resistant CLL
Developing Molecular Targeted Agents for Hepatobiliary Cancer
Two Novel Small Molecules Designed at OSU Enter Phase I Clinical Trials
Recognitions, Honors & Awards (2008 & 2009)
R21 Quick Trial NCI Grant
The R21 Quick Trial NCI Grant was awarded for correlative science of clinical trials.
Discoveries & Inventions
Anti-Cancer Compound Invention
Two compounds were invented and developed in conjunction with the Molecular Carcinogenesis & Chemoprevention Research Program, and the ET is now licensed and progressing toward clinical development.
Based on studies in Dr. Michael Grever’s and Dr. David Lucas’ laboratories, A. Douglas Kinghorn, PhD, DSc, chemically identified Silvestrol, a unique agent obtained from Malaysian plant material. NCI has accepted Silvestrol, a selective inhibitor for translation initiation of Mcl-1, into the Developmental Therapeutics Program for preclinical studies.
The agent maintains selective effects against malignant B cells while sparing normal immune effector lymphoid cells. It also demonstrates impressive in vivo anti-tumor activity against malignant lymphoid murine models.
New Pharmacologic Approach for Flavopiridol Delivery
ET investigators developed a new pharmacologic approach for Flavopiridol delivery, rescuing the early clinical development of this cyclin-dependent kinase inhibitor as an effective new therapy for advanced chronic lymphocytic leukemia. The investigators identified the extensive plasma protein binding of the agent, which is one of the most effective agents in treating resistant CLL.
The new pharmacologic approach for the cdk inhibitor’s delivery has shown remarkable clinical activity, with an overall response rate of 45 percent in heavily pretreated patients with bulky disease associated with poor cytogenetics.
A multi-institutional Phase II trial is now underway with pharmaceutical sponsor Sanofi-Aventis. The NDA-directed trial is also being completed in an international study based upon work done by ET members John Byrd, MD, and Michael Grever, MD.
Additionally, researchers in Dr. Byrd’s laboratory have launched a Phase I trial of cdk inhibitor to compare results to those from Flavopiridol for patients with lymphoid malignancies.
New PI3 Kinase Inhibitor Identified
ET member John Byrd, MD, has identified a highly active new agent, CAL101, a PI3 kinase inhibitor. Patients in the early Phase I studies have responded and his laboratory is exploring this target’s mechanistic validation.
New Class of Quinoline-Based DNA Hypomethylating Agents
An ET research group led by Samson Jacob, PhD, and collaborating with Supergen, Inc., identified a new class of quinoline-based DNA hypomethylating agents that can re-activate epigenetically silenced tumor suppressor genes. The new agents are not incorporated into DNA and are therefore potentially less toxic than 5-Aza compounds. They can also re-express the TS genes in solid tumor and leukemia cells as well as in primary CLL cells in vitro.
Decitabine and the Elderly
ET member John Byrd, MD, and colleagues in the Division of Hematologic Malignancies have successfully utilized low doses of decitabine to induce remissions in elderly patients with acute myeloid leukemia. Guido Marcucci, MD, and William Blum, MD, have conducted several pivotal studies to define the optimal dose and drug administration schedule.
ET investigators collaborate with several OSUCCC–James Shared Resources, including
the Biostatistics Shared Resource, which is integral to the success of many of the ET’s new endeavors, as well as the Clinical Trials Shared Resource - another heavily utilized SR in many ET funded studies, and the Nucleic Acid Shared Resource, the Cytometry Shared Resource and the Pharmacoanalytical Shared Resource.
Other collaborations include:
ET Co-Leader Samson Jacob, PhD, and Sarmila Majumder, PhD. in collaboration with Bhuvaneswari Ramaswamy, MD, and Cancer Control member Charles Shapiro, MD, recently demonstrated that microRNAs 221/222 impact primary breast tumors’ resistance to Tamoxifen. The relatively high levels of these miRNAs are potentially useful in diagnosing the emergence of Tamoxifen-resistant breast cancer.
ET Co-Leader Samson Jacob, PhD, and ET member Kalpana Ghoshal, PhD, collaborated with ET members Tushar Patel, MB ,ChB.; Thomas Schmittgen, PhD; and MBCG member Carlo Croce, MD, to identify specific miRNAs (including inflammation-specific miR155) that are dysregulated at various stages of hepatocarcinogenesis. The study not only demonstrated the miRs’ deregulation for early HCC diagnosis, but it also revealed the potential for applying specific anti-miRs in HCC therapy.
- ET Co-Leader Michael Grever, MD, engaged OSU Department of Chemistry faculty to collaborate with OSUCCC investigators
- ET Co-Leader Michael Grever, MD, has engaged OSU Department of Pharmacy faculty to collaborate with OSUCCC investigators on several collaborative efforts, including:
- The ET brought two new agents from the bench to early trials in man. Ching-Shih Chen, PhD in MCC, OSU College of Pharmacy, designed two novel chemical structures and has received FDA approval for an IND in both agents.
- The ET has collaborated with the OSU Department of Pharmacy’s A. Douglas Kinghorn, PhD, DSc, who chemically identified a unique agent obtained from Malaysian plant material. Based on studies in Dr. Michael Grever’s and Dr. David Lucas’ laboratories, Dr. Kinghorn identified Silvestrol, and the ET was instrumental in helping Dr. Kinghorn’s team secure the P01 in Natural Products Discovery. Additionally, the NCI has accepted the agent into the Developmental Therapeutics Program for isolation and preclinical studies.
- ET member Tanios Bekaii-Saab, MD, collaborated with Vaccine Development Program Director and Innate Immunity member Pravin Kaumaya, PhD, to successfully complete the NCI-funded Phase I active immunotherapy study on first generation B-cell chimeric and multi-epitope based peptide vaccines targeting HER-2 Oncoprotein and nMDP adjuvant in patients with metastatic or recurrent solid tumors. “The Journal of Clinical Oncology” accepted the study for publication in 2009.
- ET member Miguel Villalona, MD, is collaborating with OSU Department of Pharmacology member Roger Briesewitz, PhD, and Department of Clinical Pathology faculty Weiqiang (John) Zhao, MD, PhD, to sequence receptor tyrosine kinase sites associated with lung cancer. The objective is to identify and personalize patient treatment based on the inhibitor most likely to produce a beneficial effect.
- ET member Miguel Villalona, MD, is collaborating with OSU Department of Pharmacology member Roger Briesewitz, PhD, and the OSU Chemistry Department to develop K-ras mutant targeted agents, based on a novel and patented concept, to bring to the clinic.
The ET supported the successful award of a program project in:
- Thyroid cancer and Chronic Lymphocytic Leukemia (CRC Research Consortium for new therapies in CLL) – Michael Grever, MD, principal investigator
- Natural Products Discovery – A. Douglas Kinghorn, PhD, DSc, principal investigator
- Numerous R01 and R21 Grants
- NCI Leukemia Spore Grant
- University of California, San Diego: ET Co-Leader Michael Grever, MD, is a principal investigator on a project for Pharmacology and Experimental Therapeutics for a P01 in collaboration with University of California, San Diego.
- University of Cincinnati Department of Pediatrics: The ET will partner with UCDP basic scientists and their colleagues in the cancer center to study new molecules of interest in cancer therapy.
- National Cancer Institute: The ET continues to collaborate with the NCI to test the effect of the PARP inhibitor ABT-888 on cancer cells and fibroblasts deficient in this pathway and to identify synergistic molecules. A human trial using selection by this strategy to treat cancer patients is approved and supported through a grant by the NCI/CTEP ACTNOW program.
- Cancer Therapy Evaluation Program/NCI: ET member Tanios Bekaii-Saab, MD, collaborated with CTEP and successfully conducted two Phase II trials in hepatocellular and biliary cancers, both of which were also part of a larger collaborative effort with multiple OSU basic scientists.
- The first study investigated the dual EGFR/Her2-neu inhibitor, lapatinib, in HCC patients and has now been accepted for publication at Clinical Cancer Research.
- Dr. Bekaii-Saab successfully completed the second study: investigating the role of the MEK inhibitor AZD6244 in patients with advanced biliary cancers. This study’s results generated significant interest in the scientific community and were presented at the NCI/CTEP as well as at the 2009 American Association for Cancer Research meeting.
- Oncolytics Pharmaceuticals: ET member Miguel Villalona, MD, is collaborating with Oncolytics Pharmaceuticals to study a virus that replicates in ras-activated cells and potentially effective ras-activated inhibitors. Dr. Villalona is studying this therapeutic approach in lung cancer, and the NCI-CTEP has approved a concept for a study in pancreatic cancer. The pancreatic cancer studies will be in collaboration with ET member Tanio Bekaii-Saab, MD.
- Supergen Collaboration: In collaboration with Supergen, Inc., an ET research group led by Samson Jacob, PhD, identified a new class of quinoline-based DNA hypomethylating agents that can re-activate epigenetically silenced tumor suppressor genes. The new agents are not incorporated into DNA and are therefore potentially less toxic than 5-Aza compounds. They can also re-express the TS genes in solid tumor and leukemia cells as well as in primary CLL cells in vitro.