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Research Programs

2012 ACS IRG Recipients

This is the seventh year of an American Cancer Society Institutional Research Grant (ACS IRG) that was awarded to the University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC) to support promising new research by junior faculty members. The following are the grant awardees for 2012:

PI: Arnob Banerjee, M.D., Ph.D.

Project Title: Combining transcriptome and exome sequencing in T cell lymphoma

Description of Research Proposed:

High throughput genomic sequencing in several types of cancer has identified previously undiscovered mutations, revealing potential for the development of novel cancer therapies. One of the great present challenges in cancer research is to translating this genomic knowledge into therapeutic use (1). Distinguishing the mutations that contribute to cancer biology (drivers) from non-pathogenic (passenger) mutations and determining the effects of each driver mutation will require functional analyses. High throughput approaches to assigning function to cancer gene mutations are currently under development (2, 3). Large-scale approaches can compensate for the little functional information that currently exists regarding the majority of gene products. Compared to most cell types, there is an abundance of published work on T lymphocyte signaling, proliferation, apoptosis, and differentiation. The abundance of research on T cells, and the parallels between peripheral T cell lymphoma (PTCL) cells and their normal T cell counterparts make PTCL a disease in which the gap between genomic sequence data and functional cancer biology may be more easily bridged. PTCL is notable for a rising annual incidence, poor prognosis, and an overall lack of consensus on optimal treatment (4). Over the last year we have initiated a project to identify mutations in all exons (exome) in PTCL and to conduct functional molecular studies to determine key driver mutations. The project is developing well, and we recently won an award from the Gabrielle's Angel Foundation for Cancer Research to fund a portion of the work (not including the work proposed in this application). While our traditional molecular biology approach to identifying the consequences of specific PTCL mutations bears promise, complementing it with a high throughput mRNA transcript sequencing (RNA seq) approach will increase our productivity tremendously. Through the aims below we propose to combine exome sequence data and RNA seq data in PTCL as a high throughput approach to determine the functional consequences of specific PTCL mutations.

Cancer-Related Category: (UM, B) Medicine, Medicine. Combining transcriptome and exome sequencing in T cell lymphoma.

Award Amount: $30,000

PI: Maricel Kann, Ph.D.

Project Title: Mapping the interaction network of cancer proteins

Description of Research Proposed:

The fight against cancer has been hindered by its highly heterogeneous nature. Recent genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare cancer somatic mutations present only in a small fraction of lesions. For instance, the genome of a colorectal cancer in one patient can have somewhere between 50 to 100 somatic mutations, but might share only 2 or 3 mutated genes with colorectal tumor genomes from other patients. Somatic mutations that are frequently found in tumor genomes often play a significant role in tumor development and are thus classified as cancer driver mutations. However, efforts to correlate somatic mutations found in one or few individual tumor genomes with critical functional roles in tumor development have so far been unsuccessful. The significance of this challenge has been recognized by the cancer community and raised as one of the 22 provocative questions by the National Cancer Institute: How can we determine which mutations have key roles in tumor development and maintenance? The broad, long-term goal of this application is to provide a new strategy for the discovery of mutations with significant roles in tumor development and maintenance that can be targeted for personalized therapeutic approaches.

Cancer-Related Category: Renewal. (UMBC) Biological Sciences. Mapping the interaction network of cancer proteins.

Award Amount: $30,000

PI: Fengtian Xue, Ph.D.

Project Title: Development of Novel Kaiso Inhibitors as Drug Candidates for Human Colon Cancer

Description of Research Proposed:

The overall aim of this proposal is to develop drug-like Kaiso inhibitors with inhibition constants in the nanomolar range as drug candidates for the treatment of human colon cancer.

Kaiso is a ubiquitous BTB/zinc finger transcriptional repressor that is implicated in development and cancer. It functions by recruiting the N-CoR repressor complex to promote histone deacetylation and the formation of repressive chromatin structures in target gene promoters. In cells, Kaiso plays a central role in silencing the transcription of methylated tumor suppressor and DNA repair genes. Experimental evidence has shown that Kaiso is expressed in human colon cancer,1 and its protein level increases in murine intestinal cancer (1). Recent studies have demonstrated that deletion of Kaiso showed no obvious developmental phenotype in mice (1-2). Inhibition of Kaiso reactivates the hypermethylated tumor suppressor and DNA repair genes, leading to the restallation of cellular checkpoints and making colon cancer cells susceptible to stress challenge and chemotherapeutic agents (3).

Based on the crystallographic data of the lead (C08) that has been discovered from a computer-based screening and a high-throughput biological screening process, we propose to synthesize three novel classes of inhibitors for Kaiso (Aims 1-3), designed using a novel computer-aided drug design methodology (CADD, the MacKerell laboratory). Synthesized compounds will be evaluated using a thermal scanning fluorimetry assay (TSF) in the Privé laboratory, with the top compounds from the TSF assay subjected to biological assays in the Melnick laboratory (Aim 4).

Cancer-Related Category: (UM, B) Pharm. Sciences/Pharmacy. Development of Novel Kaiso Inhibitors as Drug Candidates for Human Colon Cancer.

Award Amount: $30,000

PI: Sarah M. Temkin, M.D.

Project Title: Cervical Cancer Disparities in Maryland: The impact of access to treatment.

Description of Research Proposed:

Cancer Disparities Category: (UM, B) OB/GYN & Rep Services, Medicine. Cervical Cancer Disparities: The impact of access to treatment.

Award Amount: $30,000

This page was last updated on: March 13, 2012.