Molecular Medicine Program Scientific Highlights
The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. The inter-programmatic collaboration of Drs. Smalley KSM, Forsyth P, Koomen JM and Smalley I (CBE) used multi-omics approaches revealing how the leptomengeal microenvironment shapes the biology and therapeutic responses of melanoma cells. The studies identified molecular signatures associated with Leptomeningeal Melanoma metastases and disease resistance. Clin Cancer Res (2020); 26(9): 2163-2175. PMCID: PMC7196498
The labs of Drs. Schonbrunn and Chen (CBE) demonstrate that MDMX is a potent physiologic inhibitor of casein kinase 1a (CK1a) with roles in regulating the response to WNT/b-catenin signaling. P53 null mice expressing the MDMX(w200s/w201c) mutant, defective in CK1a binding exhibit reduced Wnt/b-catenin target gene expression and delayed tumor development. EMBO J (2020); 39(14): e104410. PMCID: PMC7361285
Dr. Rami Komrokji led a double-blind, placebo-controlled phase 3 trial demonstrating that luspatercept reduced the severity of anemia in patients with lower-risk Myelodysplastic Syndromes, who had disease that was refractory to erythropoiesis stimulating agents. This NEJM publication, where Dr Komrokji is senior author, led to FDA approval and updates to the NCCN guidelines. NEJM (2020); 382(2): 140-151. PMID: 31914241.
Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous neoplasm in which JAK2 inhibition has demonstrated reductions in inflammatory cytokines and promising clinical activity. Importantly, Drs. Padron, Fridley (CE), List and Komrokji’s groups have identified a fingerprint of inflammatory cytokines from peripheral blood plasma that is prognostic for CMML. Specifically, CMML patients with decreased IL-10 expression have a poor overall survival when compared to CMML patients, establishing cytokines such as, IL-10 as prognostically relevant and defining the CMML inflammatory state. Leukemia (2019); 33(1): 205 -216. PMCID: PMC7787307
Dr. Mark Ji’s lab has developed a series of alpha-helix-mimicking peptidomimetic disrupters of b-catenin/BCL9. The new sulfono-c-AApeptides mimic the binding mode of the a-helical HD2 domain of BCL9. Importantly, these agents are cell penetrant and have selective b-catenin/BCL9 driven cell-based anti-cancer activity. PNAS (2019); 116(22): 10757-10762. PMCID: PMC6561201 Even more impressive, the Ji lab has expanded on these studies to develop the first small molecule peptidomimetic mimetics with sub-micro molar affinity that disrupt the b-catenin/BCL9 interaction. These studies reveal an attractive approach to targeting WNT/β-catenin signaling, a frequently activated yet heretofore undruggable pathway that is activated in a broad cast of human malignancies. J Med Chem (2019); 62(7): 3617-3635. PMCID: PMC6931396
The Phase III PACIFIC study led by Dr. Jhanelle Gray has established durvalumab as consolidation chemoradiotherapy as the standard of care (SOC) for patients with unresectable, Stage III NSCLC without progression. This pivotal trial was initially derived from a Letter of Intent for an IIT to MedImmune/AZ submitted by Dr Gray in 2014. The concept was well received and this was converted over to global trial, the results of which are now published in two articles co-authored by Dr Gray for the New England Journal of Medicine (NEJM). Durvalumab is now listed in the NCCN guidelines, has received FDA approval, and has changed the standard of care for patients with unresectable NSCLC. Most recently, the three overall survival year-update was published in JTO and lead by Dr Gray. This highlights long-standing intra-programmatic success of collaboration between Dr. Gray and Dr. Alberto Chiappori as durvalumab and placebo showed a median OS of 83.1% versus 74.6%, 66.4% versus 55.3%, and 57% versus 43.5% at 12, 24-, and 36-months, respectively, further establishing the PACIFC regimen as SOC in this population. J Thorac Oncol (2019); 15(2): 288-293. PMCID: PMC7244187
The Wan lab reported that AMP-activated protein kinase (AMPK), which coordinates energy status in relationship to energy starvation, affects epigenetic machinery to control tumor cell growth. Mechanistically this occurs through phosphorylation of the histone methyltransferase EZH2. This suggests that agonists of AMPK could be important in the context of therapeutics that target EZH2. Mol Cell (2018); 69(2): 279-291.e5. PMCID: PMC5777296
Lawrence lab demonstrated that a allosteric SHP2 inhibitor SHP099 could inhibit SHP2 mutants found in leukemia. They synthesized SHP099 and demonstrated activity against cells with the SHP2 E69K mutation, while three other SHP2 mutants were resistant to SHP099. This study suggests that other SHP099 analogs are necessary to control leukemic cell growth for non-E69K mutations in SHP2. Leukemia 2018 May; 32: (5) 1246-1249. PMCID: PMC6166654
TNBC, has a disproportionally higher incidence in Black populations, characterized by earlier onset, late stage at diagnosis, and aggressive disease. Dr. Heather Han led a large phase II study that examined veliparib with chemotherapy in BRCA1/2 mutated breast cancer in which she enrolled the most patients internationally. Based on the promising results of this trial (Annals of Oncology (2018); 29(1): 154-161. PMCID: PMC5834075), she was invited to serve on the Global Steering Committee for the phase III trial which confirmed that the addition of veliparib to carboplatin/paclitaxel led to improved overall response rate, particularly for those with TNBC. These results were presented at the 2019 ESMO Presidential Symposium and published in The Lancet Oncology (Lancet Oncology (2020); 21(10): 1269-1282. PMID: 32861273) with Dr Han as a lead author, with plans for a future possible FDA submission.
While the Bruton’s tyrosine kinase inhibitor ibrutinib has excellent activity associated with high response rate in B-cell lymphomas, a number of patients relapse with drug resistant disease. The Tao lab used organotypic drug screening alongside chemical proteomics to demonstrate the role of the tumor microenvironment in ibrutinib resistance (Nat Commun, (2017); 8: 14920. PMCID: PMC5399304). The demonstrated that the tumor microenvironment leads to adaptive reprogramming of the kinome, bypassing the effects of ibrutinib, and restoring activity of the PI3K/Akt/mTor pathway. Addition of inhibitors of PI3K/Akt/mTOR to ibrutinib reverses drug resistance and enhances activity of ibrutinib in patient samples of mantle cell lymphoma and in PDX mouse models of mantle cell lymphoma. These results suggest a new combination treatment strategy.
Castration-resistant prostate cancer (CRPC) defines the incurable stage of disease. While the second-generation antiandrogen enzalutamide and the androgen-synthesis inhibitor abiraterone stall CRPC progression for a limited time, tumors inevitably develop resistance by replenishing either the androgen receptor (AR) or its spliced variant AR-V7, which lack the ligand-binding region. The Mahajan* lab uncovered ACK1 kinase as an epigenetic modifier hijacked by AR to modify its own gene locus, reactivating AR mRNA synthesis by a mechanism involving ACK1 phosphorylation of histone H4 at tyrosine 88 up-stream of the AR transcription start site (Cancer Cell (2017); 31(6): 790-803. PMCID: PMC5512571). In collaboration with the Lawrence lab, developed the novel ACK1 inhibitor (R)-9bMS that blocks pY88-H4 epigenetic marks, and sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. This study demonstrates an epigenetic mechanism of tyrosine kinase-driven CRPC growth and suggests a new therapeutic strategy.
Dr. Jon Strosberg was the lead author on a New England Journal of Medicine article that studied the efficacy and safety of lutetium-177-dotate for patients with advanced, progressive, somatostatin-receptor positive midgut neuroendocrine tumors (NEJM (2017); 376(2): 125-135. PMCID: PMC5895095). Treatment with 177-Lu-Dotate resulted in higher response rates and progression free survival, with suggestions in the early analysis of an improvement in overall survival.