2019 Chabner Colloquium
Session 1:
Promising New Targets for Drug Discovery and Development
(Overview) IDH Inhibition in Acute Myeloid Leukemia – Emergence of a New Therapeutic Era
Amir Fathi, MD
MGH/Harvard Medical School
2HG, elevated in patients with IDH mutations, can also be measured in the serum and urine of affected patients, where it can serve as a biomarker of disease activity and therapeutic response. These advances triggered development of a new class of small molecule inhibitors of mutant IDH enzymes. After demonstrating promising anti-leukemic activity in animal models, phase 1 and 2 clinical trials of IDH inhibitors followed. Trials of the IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib demonstrated single agent activity, response rate, transfusion independence, and long-term outcomes.
Lecture Slides
Full Lecture Audio
Clonal Hematopoiesis
Benjamin Ebert, MD, PhD
Dana-Farber Cancer Institute
Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-associated condition in individuals who do not have a hematologic malignancy or altered blood counts. Consistent with the concept that CHIP is a pre-malignant state, CHIP is associated with a striking increased risk of hematologic malignancy. In addition, individuals with CHIP have increased overall mortality and an increased risk of cardiovascular disease.
Lecture Slides
Full Lecture Audio
(Overview) Epigenetic Reversal of Chemotherapy Resistance in Cancers
Mo Motamedi, PhD
MGH Cancer Center
Cancer recurrence and resistance to radiation and chemotherapy are two of the most vexing challenges in cancer treatment, resulting in burgeoning healthcare costs and, more problematically, fatalities every year. A contributing factor is the natural and stress-induced emergence of a subpopulation of tumor cells which is resistant to treatment, often entering into a special cellular state called quiescence (G0). Recent work has revealed that constitutive heterochromatin proteins play a conserved role in G0 and longterm stress resistance in mammalian cells, where they also help establish their adaptive transcriptional program.
Session 2:
Junior Faculty Forum
(Overview) ctDNA, a Biomarker of Residual Disease and Tumor Response in Gastrointestinal Cancers
Aparna Raj Parikh, MD
Massachusetts General Hospital
Monitoring ctDNA is a promising new approach to personalized cancer medicine that may provide real-time information about the evolution of tumors. We evaluated how changes in ctDNA predicted response to treatment across metastatic gastrointestinal cancer patients on treatment and compared ctDNA to standard tumor markers. Longitudinal ctDNA assessment both in the curative and metastatic settings may provide insight into the dynamic changes due to treatment.
Lecture Slides
Full Lecture Audio
(Overview) Cross-resistance in Small Cell Lung Cancer
Benjamin Drapkin, MD, PhD
MGH Cancer Center
We have generated a panel of 66 patient-derived xenograft models (PDXs) of SCLC from biopsy specimens and circulating tumor cells (CTCs). These models stably maintain somatic genomic alterations from patients, and faithfully mirror their responses to DNA damaging therapies. The strongest correlate with sensitivity to both regimens was basal expression of interferon-stimulated genes (ISG’s), and cross-resistance was marked by low basal ISG expression. This result was surprising, as xenografts were grown and tested in severely immunocompromised mice. Investigation of the ISG signature presents a novel opportunity to dissect the molecular underpinnings of cross-resistance, a problem
Lecture Slides
Full Lecture Audio
(Overview) RET As a Target in Lung Cancer
Jessica J. Lin, MD
Massachusetts General Hospital
Rearranged during transfection (RET) proto-oncogene rearrangements have been validated as an additional oncogenic driver that occurs in 1-2% of NSCLC. Prior efforts to target RET in lung cancer patients were hampered by the lack of potent and selective RET tyrosine kinase inhibitors (TKIs), necessitating the re-purposed use of multikinase inhibitors such as cabozantinib or vandetanib, which are encumbered by suboptimal efficacy and significant toxicities. Recently, novel, oral, highly potent, and selective RET TKIs—BLU-667 (pralsetinib) and LOXO-292 (selpercatinib)—have entered the clinic.
Lecture Slides
Full Lecture Audio
(Overview) Targeting SWI/SNF-Hippo Axis in Squamous Cancers
Srinivas Vinod Saladi, PhD
Massachusetts Eye and Ear Infirmary, MGH,
HMS, Broad Institute
Squamous cell carcinoma (SCC) remains among the most treatment-refractory of human cancers, reflecting in part a limited understanding of the key pathways and mechanisms that drive this disease. The p53-related transcription factor p63 is a central tumor maintenance factor subject to overexpression and/or genomic amplification in majority of SCCs. Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. We have identified ACTL6A, subunit of SWI/SNF chromatin remodeling, as frequently co-amplified and highly expressed together with p63 in head and neck, and lung squamous cell carcinoma (HNSCC & LUSC).
Lecture Slides
Full Lecture Audio
Keynote Address
(Overview) Innovations in Cell Therapy
Marcela Maus, MD, PhD
MGH Cancer Center
Autologous T cells that have been genetically redirected with chimeric antigen receptors (CARs) specific to the CD19 antigen have achieved remarkable success in inducing rapid and sometimes complete eradication of B cell leukemias and lymphomas. New forms of CARs, including those targeting new surface molecules alone and in combination with additional functionalities, are under intense investigation. We will discuss some of our innovations in cell therapies, including strategies designed to overcome tumor heterogeneity and the tumor microenvironment.
Lecture Slides
Full Lecture Audio
STO gratefully acknowledges educational grant support from:
Celgene Corporation
Novartis Pharmaceuticals Corp.
Pfizer Inc.
