The scientists and clinical investigators within the Division of Hematology Oncology and Bone Marrow Transplant focus on understanding the molecular basis of cancer, with the overall goal of developing new and better treatments. The Division of Hematology Oncology and Bone Marrow Transplant is directly involved with the University of Cincinnati Cancer Institute’s Clinical Trials and the Cincinnati Cancer center scientific programs.
Interests of the research faculty include the design and execution of clinical trials and laboratory research on several topic, including oncogene-depended intracellular signaling, cancer metabolism, cancer immunotherapy, functional genomics and role of tissue factor in cancer biology.
Our current key research activities are briefly outlined below.
Hemostasis Research Program:
Research in the laboratory of Vladimir Bogdanov, PhD, spans basic and translational cancer research, vascular biology, and post-transcriptional regulation of gene expression. The first area of focus comprises biological functions of Tissue Factor splice variants, as well as the roles they play in the progression of solid malignancies and in cancer-associated thrombotic disorders. The second area of focus comprises mechanistic contributions of erythrocytes to the development and propagation of systemic pro-inflammatory states in settings such as diet-induced obesity.
Prostate cancer Biology:
The laboratory of Zhongyun Dong, MD, PhD, focuses on prostate cancer with the goal to further understand the molecular mechanisms underlying cancer development and progression and to develop novel therapies against this disease. The lab has shown that TGF-b-regulated IL8 expression contributes to tumor angiogenesis and cancer progression and that adenoviral vector-mediated intratumoral delivery of IFN-b, through inhibition of tumor angiogenesis, could be an effective therapy for advanced prostate cancer. The lab also identified several novel small molecule compounds targeting androgen receptor, microtubule, and proliferating cell nuclear antigen, and demonstrated the therapeutic effects of the compounds in mouse models of human prostate cancers.
Proteasome-based Therapies in Hematologic Malignancies and Plasma Cell Disorders:
The research in the laboratory of James Driscoll, MD, PhD, focuses on the identification of novel targets to treat plasma cell-related disorders. Deregulation of plasma cell biology contributes to the hematologic malignancy multiple myeloma (MM) as well as antibody-mediated rejection. The research goal is to coalesce assets from diverse disciplines with expertise, resources and techniques to enhance the development of novel therapeutics that more effectively deplete unwanted plasma cell populations. We have developed highly sophisticated genomic, bioinformatic, and cellular tools to decipher heterogeneity of plasma cell populations and have reveal molecular vulnerabilities that can be pharmacologically exploited to overcome drug resistance. Our studies have been successfully translated from bench-to-bedside in recent clinical trials (NCT02442648).
mTOR Signaling, Cancer and Autophagy Lab:
Research in the laboratory of Carol Mercer, Ph.D., is focused on the mammalian target of rapamycin (mTOR) pathway and the regulation of autophagy. Our long-term goal is to understand the mechanisms that regulate autophagy and the therapeutic implications of targeting autophagy in cancer. This is important because (1) autophagy has been argued to either inhibit or promote tumor survival; and (2) autophagy is induced by mTOR inhibitors, which are used in cancer therapy. Our project in hepatocellular carcinoma (HCC) revealed that phenformin and metformin inhibit autophagy, despite their ability to also inhibit mTOR. In addition, we are pursuing a breast cancer project, with the identification of a novel selective autophagy receptor, using high-resolution mass spectrometry proteomics. We are currently studying the significance of mTOR-regulated selective autophagy in the growth and survival of breast cancer cells.
Experimental Therapeutics Program:
Director: John C. Morris, MD; Physicians: Trisha Wise-Draper, Muhammad Riaz MD, Suchi Gulati, MD.
The Division offers a wide portfolio of clinical trials that bring new cancer drugs to the clinic. The Experimental Therapeutics Program conducts phase-1 and early phase clinical trials at the University of Cincinnati Cancer Institute. These types of trials are the first step in moving new pharmaceutical compounds, often developed by UC scientists, and are intended to evaluate safe dosages, method of administration and potential anti-tumor effects. In addition, the experimental therapeutic program co-ordinates the execution of later phase clinical trials that are sponsored by federal agencies, private foundations, pharmaceutical companies and private entities. These trials are conducted to determine whether a new drug is efficacious. Faculty members:
Immune Therapy Strategies for Cancer:
The laboratory of John C. Morris, MD focuses on the development of therapeutic strategies for lung cancer and the use of immune stimulating cytokines and vaccines to stimulate the immune system to prevent or destroy lung cancer stem cells cancer.
Theragnostic Drug and Biomarker Discovery and Development:
The laboratory of Xiaoyang Qi, PhD focuses on cell membrane phosphatidylserine (PS) as a unique and specific target for cancer therapy and diagnosis. The lab has demonstrated: 1. cancer cell surface PS is critical for creating the TLR2/6-dependent immune-deficient environment that allows tumors to grow and metastasize and to induce drug- and radio-resistance; 2. tumor cells with higher surface PS are more sensitive to the cytotoxicity of various lipid nanovesicles, especially SapC-DOPS (BXQ-350, Bexion Pharmaceuticals), a drug composed of the natural protein, saposin C (SapC) and dioleoylphosphatidylserine (DOPS), which is a PS-specific targeted and potent therapeutic agent in preclinical and clinical studies. This stable drug formulation was originally discovered and developed in Dr. Qi’s laboratory and a phase I clinical trial (NCT02859857) has recently been completed showing a very strong safety profile.
Energy Metabolism in Cancer:
To decode the cellular dynamics altered in cancers for developing new therapeutics, the laboratory of Atsuo Sasaki, Ph.D. is investigating the cellular mechanisms that detect and control the levels of GTP, an energy source critical to support rapid cancer growth. His team identified PI5P4Kβ as the culprit, establishing it as the first GTP energy-sensing kinase ever discovered. The team is now exploring potential therapeutic applications of the research while continuing to investigate the molecular pathways that PI5P4Kβ uses to gauge and manipulate GTP levels.
The laboratory of Dr. Scaglioni, MD, integrates the use of mouse cancer models, cancer cell lines, small molecule inhibitors, RNAi and CRISPR technologies to identify cancer networks that represent novel targets for therapy. The focus of research is the KRAS and MYC oncogenes, which play a pivotal role in cancer. The lab identified several cellular networks that represent novel therapeutic targets in lung cancer, such as Focal adhesion kinase, the XPOI nuclear export receptor and fatty acid metabolism. In addition, the lab determined that the SUMO E3 ligase PIAS1 is a critical regular of MYC in B-Cell lymphomas. These findings led to several clinical trials (NCI identifiers NCT01951690, NCT03095612).
The laboratory of Drs. Wise-Draper and Takiar primarily focuses on mechanisms that mediate resistance to therapy in Head and Neck Cancer. Using patient samples including blood and tissue from clinical trials before and after therapy (radiation, targeted drugs, immunotherapy, etc.) allows for a unique opportunity to study the positive and negative effects of treatment on tumor cell signaling, molecular changes, genomics as well as impact on the cancer microenvironment. Particular focuses include the DEK oncogene and the interaction between carcinogenesis and the immune environment. The laboratory utilizes patient derived xenografts (PDX) and is developing patient derived organoids (PDO) to study possible therapies to overcome resistance identified in patient samples. Several clinical trials for which samples are obtained are ongoing and new trials have been developed from these preclinical findings (NCI identifiers NCT02641093, NCT03122197, NCT03355560, NCT02325401).