Anabolic Resistance in Cancer Cachexia
Cancer cachexia is associated with a number of cancer types and results in unwanted weight loss and profound reductions in patient quality of life. Cachexia is driven by complex interactions between tumors and their patient host resulting in metabolic derangements and involuntary losses in muscle mass. Cachectic cancer patients are also frequently refractory to anti-cancer therapy and patient frailty contributes to increased chemotherapy associated toxicity. Despite up to 20% of all cancer deaths being potentially attributable to cachectic symptomology, there are no known effective treatments. Anabolic therapies are well characterized for their ability to build muscle mass but have failed to protect body composition in large clinical trials of advanced cancer patients. Our group has characterized resistance to anabolic therapies in murine models of cancer cachexia (Liva and Tseng et al, 2020). We are currently studying anabolic resistance mechanisms as a means to reveal new anti-cachectic drug targets.
Project Funded by: Eli Lilly Pharmaceutics Graduate Fellowship Program; American Foundation of Pharmaceutical Education; Pelotonia Idea Award and the Molecular Carcinogenesis and Chemoprevention Program, OSU Comprehensive Cancer Center.
Therapeutic mAb Disposition in Cancer Cachexia
Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy across a wide range of cancer types. However, less than 25% of patients typically respond to these therapies and there exits little understanding of why patient responses are so variable. Recent clinical data have demonstrated that high baseline clearance (CL0), independent of drug exposure, significantly associates with shorter overall survival in patients receiving monoclonal antibody (mAb) anti-PD-1 ICI therapies. Patients with cancer cachexia tend to have higher CL0 of mAb drugs and less favorable outcomes, suggesting that CL0 may predict ICI therapy outcomes, and that cachectic signaling may be the link between elevated CL0 and poor response (Coss et al, 2018). We recapitulated these clinical findings in well-established animal models of cancer cachexia, C-26 and LLC. In collaboration with OSU investigators Tom Mace, PhD and Dwight Owen, MD we are now exploring possible mechanisms for this phenomenon of increased CL0 and decreased ICI therapeutic response.
Project Funded by: Molecular Carcinogenesis and Chemoprevention Program, Leukemia Research Program, OSU Comprehensive Cancer Center.
Novel Combination Anti-Cachexia Therapies
The ideal goal of anti-cachectic therapy is returning patient body composition and muscle function to a pre-cachectic state. Recent studies suggest that cachectic signaling, and therefore anabolic resistance, may occur much earlier in the course of neoplastic disease than once realized. Therapies designed to limit skeletal muscle degradation have shown little ability to restore muscle mass once lost and anabolic therapies are yet to demonstrate efficacy in cachectic patients. When considered together, these findings support the development of combined anabolic and anti-catabolic therapeutic approaches. Our lab recently discovered the ability of a novel HDAC inhibitor to license anabolic activity through blockade of IL-6 mediated catabolic signaling (Liva and Tseng et al, 2020). We are currently studying how cachexia dependent inflammatory signaling contributes to anabolic resistance and exploring novel combination anti-cachexia therapeutic approaches.
Project Funded by: Eli Lilly Pharmaceutics Graduate Fellowship Program; American Foundation of Pharmaceutical Education; Pelotonia Idea Award and the Molecular Carcinogenesis and Chemoprevention Program, OSU Comprehensive Cancer Center.
PopPK/PD Modelling of Cytopenias Associated with Melphalan Therapy in Multiple Myeloma
Multiple Myeloma is the second most common hematological malignancy and is responsible for nearly 13,000 deaths annually in the US alone. High dose melphalan combined with autologous stem cell transplant (HDM-ASCT) remains the standard of care for eligible myeloma patients, despite the recent advancements in novel therapies, such as immunomodulatory drugs, proteasome and histone deacetylase inhibitors, and monoclonal antibodies. Within the last several years, the role of the bone marrow microenvironment in myeloma growth and survival has been more widely appreciated – the bone marrow contains highly specialized anatomical niches that present a milieu of cytokines, growth factors, and adhesion molecules now recognized as being critical for disease progression, including IL-6 and SDF-1. Speculation suggests that the interactions between residual myeloma and grafted CD34+ cells within the bone marrow immediately following high dose melphalan and autologous stem cell transplant provide contributing mechanisms of efficacy and resistance in this treatment regimen. Nearly every myeloma patient undergoing HDM-ASCT will experience a severe grade of pancytopenia, including neutropenia and thrombocytopenia, and one potential, high-level approach to describe the effects of melphalan and the stem cell graft on the resident cells of the bone marrow is to study post-transplant platelet counts. We have found that the below average area calculated over the curve of platelet counts vs. time and below the line of severe thrombocytopenia (20*109 cells/L; AUL) was significantly associated with longer progression free survival in a recent standard of care clinical trial at Ohio State (OSU11055, NCT01653106). (Cho and Irby et al, 2018) We are now exploring the potential of pharmacometrics tools (pharmacokinetic/pharmacodynamic modeling) to aid in prospective dose adjustments in this treatment regimen based on the prediction of a target AUL.
Project Funded by: Eli Lilly Pharmaceutics Graduate Fellowship Program; Multiple Myeloma Opportunities for Research and Education (MMORE); Pelotonia Idea Award and the Leukemia Research Program, OSU Comprehensive Cancer Center.
Androgen Receptor (AR) in Hepatocellular Carcinoma (HCC)
HCC is the predominant form of primary liver cancer and is currently the second leading cause of cancer death worldwide. HCC incidence is at least 3-fold higher in men than women supporting the role of sex hormone signaling in the disease. Previous work using hormone ablation or AR genetic knock out mice suggested androgens have causative role. However, anti-androgen therapies evaluated to date have not provided any clinical benefit. Our lab has discovered the expression of variant forms of the androgen receptor in HCC that do not respond to classical steroid competitive anti-androgen treatment (Dauki at al, 2019). In collaboration with OSU investigators James Blachly, MD, Mohamed Abdel-Rhaman, MD PhD and Tom Li PhD, we are currently studying the origins of these variants in diseased liver, the biological consequences of their signaling, and novel anti-AR therapeutic strategies that may effectively target the androgen receptor in HCC.
Project Funded by: National Cancer Institute (K12-CA133250); American Cancer Society (IRG-67-003-50); American Foundation for Pharmaceutical Education; Molecular Carcinogenesis and Chemoprevention Program, OSU Comprehensive Cancer Center.
Novel Selective Estrogen Receptor Modulators (SERMS) for the Treatment of Pre-Cancerous Liver Disease
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver morbidity afflicting 30-40% of American adults. In many patients, NAFLD to progresses to non-alcoholic steatohepatitis (NASH) which in turn progresses to HCC. NAFLD-NASH is expected to become the predominate pre-cancerous liver disease within the decade. Much like HCC, NAFLD-NASH is sexually dimorphic with males more frequently afflicted than females. This dimorphism regresses after menopause strongly suggesting a protective effect for estrogen signaling. Estrogen Receptor β (ERβ) selective ligands offer potentially therapeutic estrogen pharmacology with reduced risk of side effects associated with Estrogen Receptor α (ERα) activity. Our lab is currently evaluating a series of novel ERβ-selective SERMS originally developed within the College of Pharmacy in collaboration with the Comprehensive Cancer Center’s Drug Development Institute. We are utilizing multiple preclinical models of NAFLD-NASH to interrogate estrogen biology in hepatic disease and to inform the selection of novel therapeutic estrogens.
Project Funded by: National Cancer Institute (T32-CA009338-40); Molecular Carcinogenesis and Chemoprevention Program, Drug Development Institute, OSU Comprehensive Cancer Center.
Mechanisms of Resistance to Immunomodulatory Therapies
The immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, play a critical role in the treatment of multiple myeloma. In combination with other agents, outcomes for multiple myeloma patients have been greatly improved with IMiD therapy. Unfortunately, nearly all patients develop resistance to these agents, though the mechanisms of resistance remain largely uncharacterized. Our lab is working on understanding the role drug transport may play in IMiD resistance. We are in search of transporter(s) potentially responsible for the differences observed in drug disposition among the three IMiDs across multiple in vitro and in vivo studies (Rozewski et al 2012).
Project Funded by: National Cancer Institute (R01-CA201382); Leukemia Research Program, OSU Comprehensive Cancer Center.
Immunoliposomes for Delivery of Novel Small Molecule and Oligonucleotide Therapies
Targeted delivery of small molecule therapies offers promise as a way to widen therapeutic windows for diverse therapeutic payloads. OSU-2S is a novel anti-cancer agent originally synthesized by our collaborators here in the College of Pharmacy that has demonstrated a previously undescribed ability to activate the phosphatase PP2A. PP2A is functionally down-regulated in several malignancies making it a promising anti-cancer therapy target. Our group has supported basic preclinical development of this agent through completion of pharmacology studies in rodents and canines. Building on the development of OSU-2S, we explored the utility of an immunoliposomal platform for targeted delivery of OSU-2S and other therapeutic agents to cancer or immune cells. This project has mainly focused on immunoliposomes loaded with OSU-2S and coated with 2A2, an anti-hROR1 antibody, in mice that express human ROR1 (hROR1) on leukemic B-cells (Mani et al, 2015). Other targeting antibodies and other immunoliposomal cargo, including microRNA and other oligonucleotide therapies are also being evaluated. This project is a close collaboration with OSU investigators Raj Muthusamy, DVM, PhD, and Robert Lee, PhD.
Project Funded by: National Cancer Institute (R01-CA197844); Leukemia Research Program, OSU Comprehensive Cancer Center.
Exosomes as Carriers for Therapeutic Oligonucleotides in Cancer
The delivery of therapeutic oligo nucleotides remains an important yet unsolved problem. Cell derived exosomes have been shown to shuttle diverse biological molecules, including endogenous oligonucleotides, from cell to cell through systemic circulation. This project aims to explore the use of cell-derived exosomes as carriers for microRNA therapies. In close collaboration with Tom Schmittgen, PhD at the University of Florida and Jeff Chalmers, PhD here at OSU, our group explored HEK293T cell derived exosomes, loaded either endogenously with miR-199 or exogenously with cholesterol-labeled antimiR-221 in mouse model of hepatocellular carcinoma. Contributions made to this project thus far have included characterization of immunogenic and toxic effects of human cell derived exosomes and biodistribution and delivery of the oligonucleotide cargo in mouse models of cancer (Xu et al, 2017).
Project Funded by: National Center for Advancing Translational Sciences (UH2TR000914 and UH3TR000914); Leukemia Research Program, OSU Comprehensive Cancer Center.