Microsymposium on the 19th of June
Welcome to the CanCell microsymposium scheduled for Tuesday the 19th of June at 14 hrs
Teresa A. Zimmers, Indiana University School of Medicine
Kapil N. Bhalla, MD Anderson Cancer Center
14.00 hrs: Kapil N. Bhalla, MD, Professor in Department of Leukemia, at The University of Texas MD Anderson Cancer Center (MDACC).
Targeting dysregulated transcriptome as therapy of Acute Myeloid Leukemia
Abstract: Although clinically effective in reducing AML cell burden, resistance to treatment with FLT3 or JAK1/2 tyrosine kinase inhibitors (TKIs) occurs commonly, eventually conferring poor clinical outcome in patients with de novo or post-MPN sAML. This aggressive biology and therapy-refractoriness in AML is determined by the dysregulated transcriptome downstream of the genetic alterations commonly encountered in treatment refractory AML. Therefore, effectively targeting of the downstream dysregulated transcriptome, dependent on the activity of the chromatin reader BET proteins (BETP) BRD4, notwithstanding the upstream genetic alterations in AML, is the focus of our present studies. BRD4 binds to the acetylated lysine on histones proteins and transcription factors and recruit co-regulatory chromatin modifying enzymes, remodeling factors and the mediator elements to the enhancers and promoters of important AML-relevant deregulated oncogenes. BRD4 regulates the mRNA transcript elongation through RNA pol II (RNP2). Acetyl-lysine mimetic BETP inhibitors (BETi), including JQ1 and OTX015, evict BRD4 from the chromatin, causing transcriptional repression of the oncogenes. Our reported findings demonstrated that treatment with BETi inhibits in vitro and in vivo growth and synergistically induce apoptosis when combined with TKIs in cultured and patient-derived (PD) AML as well as post-MPN sAML blast progenitor cells (BPCs), including those expressing mtTP53. Despite significant AML activity, BETi treatment leads to BRD4 protein accumulation over time., which may account for sub-optimal BETi-mediated transcriptional repression of AML-relevant oncoproteins and their targets, as well as in reducing BETi-induced apoptosis. To circumvent this limitation, hetero-bifunctional BETP-PROTACs (proteolysis targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc) that polyubiquitylate and proteasomally degrade BETPs, including BRD4 and BRD2, have been developled. Unlike BETis, BETP-PROTACs more potently attenuated MYC, p-STAT5, Bcl-xL, PIM1 and CDK6, as well as mediate profound growth inhibition and apoptosis in TKI-sensitive and TKI-persister/resistant AML or sAML cells. This translated into a significantly reduced AML burden and improved survival, without toxicity, in immune depleted (NSG) mice engrafted with AML and treated with ARV-771 and TKI. Resistance to BETi has been documented to be due to nuclear β-catenin-TCF4 mediated c-Myc induction in AML BPCs. Our findings demonstrate that BETP-PROTAC retain activity and synergistically induce apoptosis with β-catenin antagonist in BETi-persister/resistant AML BPCs. These preclinical findings highlight the promise of BETP-PROTAC-based combination therapy to target dysregulated transcription to overcome therapy refractoriness in AML.
15.00 hrs: Teresa A. Zimmers, Associate professor, founding director of the IU Simon Cancer Center Cachexia Working Group and the IUPUI Center for Cachexia Research Innovation and Therapy.
Tumor-host crosstalk in pancreatic cancer cachexia - lessons from mice to men
Abstract: Cachexia, recognized by progressive loss of skeletal muscle and adipose tissue, contributes directly to morbidity and mortality in diseases as diverse as organ failure, AIDS, burn, trauma and cancer. Indeed, cachexia itself and not other effects of the tumor is thought to be the cause of up to 1/3 of all cancer deaths. Relatively little is understood regarding the molecular and cellular pathways leading to weight loss and dysmetabolism in cachexia and currently there are no approved, effective therapies. My group, working with a large and diverse group of collaborators, seeks to fill that knowledge gap by using novel animal models and correlative phenotypic and molecular data from patients to identify molecular, cellular and organ system mechanisms leading to cachexia. In this fashion we have:
1. Identified a key role for IL-6/GP80/GP130/STAT3 in muscle and fat wasting in cancer and burns.
2. Identified a causal role for Activins in burn-induced muscle wasting and shown efficacy in targeting Activin, myostatin and GDF11 in burn cachexia.
3. Identified key roles of sonic hedgehog/GLI proteins and Smoothened in muscle wasting of cancer cachexia.
4. Developed or characterized dozens of new models of pancreatic cancer cachexia, including congenic orthotopic, patient-derived xenografts ("cachexia avatars"), and genetically engineered mouse models (GEMMs).
5. Collected thousands of biological specimens from 160 patients under study for pancreatic cancer cachexia to enable the largest profiling study in this disease to date.
6. Discovered novel targetable molecular pathways and organ cross-talk contributing to cachexia in cancer and burns.
Our current work focuses upon studying these novel molecular and organ cross-talk pathways in cell cultures and animal models. At the same time we are undertaking clinical studies in cancer cachexia. At this time we are searching for funding for a proposed clinical trial to treat cachexia in patients with pancreatic cancer as well as to examine the systemic response and rates of muscle and fat wasting in an open trial in pancreatic cancer.
CanCell by Tor Erik Rusten and Jorrit Enserink