Sunil Sharma, M.D., F.A.C.P., M.B.A.

Division Overview:

Identifying Possible Cancer-Fighting Agents

The goal of the Applied Cancer Research and Drug Discovery Division is to identify clinical candidate compounds as possible cancer-fighting agents to be considered for Phase I (first-in-man) clinical trials.

Program Features

Features of the preclinical program fall under two general categories:

1. Computational and medicinal chemistry; including computer-aided drug design
2. Cancer biology; including assay development, screening, biomarker identification and in vivo models for preclinical efficacy and imaging studies

Specific Projects in the Sharma Lab:

Immuno-Oncology
The immune system plays an important role in protecting the body against cancer by targeting and destroying foreign cells. Immuno-Oncology strategies help to restore the immune system's abilities to mobilize an immune response against the tumor. Many strategies being developed help to fight cancer by controlling the mechanisms T cells use for mounting an immune response. Others seek to stimulate an immune response helping strengthen detection and targeting of newly formed tumors, thus reducing the likelihood of further tumor growth and metastases.

We have successfully identified 60 small molecules and over 40 fragments that show binding affinity against immune system pathways. This was done using crystal structures and a focused library of our internal compound collection. These hits have been screened for enzymatic activity. The results, from target validation experiments, clearly support the pharmacological role of these targets for the development of novel immunotherapeutics for multiple cancers and are the opportunity we are proposing to complete the remainder of in-vitro and future in-vivo studies. 

Bromodomains/c-Myc – Epigenetic and transcriptional regulation, Protein interactions, Cancer Metabolism

c-Myc is a master regulator of cell proliferation and activation of c-Myc plays a role in the pathogenesis of a majority of human cancers. c-Myc is a transcription factor whose target genes are involved in cell division, metabolic effects, and survival.  The literature supports c-Myc as an attractive therapeutic target with an appropriate therapeutic index for c-Myc inhibition.  However, there are currently no small molecule inhibitors which directly inhibit c-Myc-drive transcriptional programs.  Without a clear ligand-binding domain, a direct c-Myc therapy is likely elusive. Nonetheless, c-Myc transcriptional programs can be targeted by targeting the epigenetic regulators which promote transcriptionally active chromatin at c-Myc target genes, including the bromodomain and extra-terminal subfamily members BRD2, BRD3, and BRD4 which bind acetylated histones and recruit transcriptional activators, including c-Myc.  The bromodomain inhibitor JQ-1 prevents interaction between the bromodomain of BRD4 and acetylated histone at M/G1 genes and prevents transcription of c-Myc target genes.  Indirect inhibition of bromodomain-histone association looks to be an effective indirect strategy to target c-Myc-drive transcription. The Sharma Lab is collaborating to create a screening assay for several bromodomain protein interactions with histone h2 and histone H4. We are also working on lead compound optimization based on this new screening assay. 

LSD1 – Epigenetic and transcriptional regulation, Cancer metabolism
Lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase in 2004.  Since then, dynamic histone methylation has been described as an important regulator of chromatin architecture and transcription. LSD1 is shown to be upregulated in various cancers, including breast cancer, prostate cancer, hepatocellular carcinoma, colorectal cancer, neuroblastoma, acute myeloid leukemia, and Ewing's and synovial sarcomas.  Often, high LSD1 levels predict aggressive tumor biology and poor prognosis.  LSD1 is required for normal development and differentiation, as well as maintenance of stem cell pluripotency.  Further, LSD1's role is highly context dependent and is determined by which nuclear complexes it associates with.

In order to better understand LSD1's role in cancer and whether LSD1 inhibition represents a therapeutic strategy, the lab has developed a novel series of potent, selective, and reversible inhibitors against LSD1.  We are currently exploring the epigenetic and transcriptional changes associated with treatment in vitro and in vivo with several solid tumor models.

Beta-Catenin/wnt signaling – Epigenetic and transcriptional regulation, Protein interactions

The Wnt signaling pathway is involved in several processes, including regulation of cell growth, motility, and survival, with the canonical Wnt pathway dependent upon beta-catenin.  However, Wnt signaling has a pathological role, with evidence that mutational activation of the canonical pathway participates in tumorigenesis.  In colon cancer mutation of APC or beta-catenin is an early event in transformation of colonic epithelial cells. Further, established colorectal cancers also depend on Wnt signaling. APC of Axin2/conductin mutations result in defective beta-catenin degradation, accumulation of beta-catenin in the nucleus, and perpetual transcription of Wnt target genes.  Mutations in beta-catenin render the protein resistant to degradation. We are focused on basic and translational studies to develop compounds which inhibit the protein-protein interactions which prevent destruction of beta-catenin and promote transcription of Wnt target genes.