Testing of novel anti-cancer compounds Curaxins against pancreatic cancer

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R41CA159657-01A1
Agency Tracking Number: R41CA159657
Amount: $300,000.00
Phase: Phase I
Program: STTR
Awards Year: 2012
Solicitation Year: 2012
Solicitation Topic Code: NCI
Solicitation Number: PA11-097
Small Business Information
73 HIGH ST, BUFFALO, NY, 14203-1149
DUNS: 830459546
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (716) 849-6810
Business Contact
Phone: (716) 849-6810
Email: bspecht@bbiolabs.com
Research Institution
BUFFALO, NY, 14263-
 () -
 Domestic nonprofit research organization
DESCRIPTION (provided by applicant): Mortality from pancreatic ductal adenocarcinoma (PDA) is close to 100% due to the absence of effective treatment approaches. This proposal is focused on determining the therapeutic potential of a new class of candidateanti-cancer agents named Curaxins (CXs) for treatment of PDA. The rationale for this is based on our discovery that CXs inhibit the activity of the Facilitate Chromatin Transcription (FACT) complex, which is overexpressed in ~60% of PDA. Inhibition of FACT by CXs leads to suppression of several stress response signaling pathways, including NF-kB and heat shock factor 1 (HSF1). This mechanism of action can be predicted to impact PDA since one of the most significant factors predisposing to PDA is chronic inflammation with constitutive activity of NF-kB. Heat shock response, mediated by HSF1, is frequently overactive in PDA cells. Our preliminary tests showed that CXs are toxic to PDA cells and tumors, including those resistant to the current standard of care, gemcitabine (GC). To meet our overall goal of advancing CXs towards clinical use for treatment of PDA, we propose the following Specific Aims: 1. To select the optimal CX compound ( CX-X ) for anti-PDA clinical development. Four CXs were selected following structure activity relationship (SAR) studies. These synthetic, structurally-related small molecules demonstrated the best in vitro activity (effects on p53 and NF-:B, toxicity to tumor cells), in vivo activity (low toxicity in mice, yet effective against tumors) and pharmacological properties. The four CXs will be tested for in vitro toxicity against a panel of established PDA cell lines as well as primary cells isolated from surgical samples of PDA separated into pancreatic cancer stem cells (PCSC) and bulk PDA cells based on expression of PCSC markers (CD24, CD44 and ESA). The CX concentration killing the majority of cells (LC90) will be determined for each cell sample. In parallel, we will measure CX accumulation in the pancreas of treated mice. TheCX molecule with the highest ratio of intra-pancreas concentration to LC90 in PDA cells ( CX- X ) will be selected for use in Aims 2 and 3. 2. To determine the efficacy of CX-X in mouse models of Gemcitabine-sensitive and -resistant PDA. Gemcitabine(GC) is currently the main agent used in patients with advanced PDA. Although GC is effective in some patients, most demonstrate intrinsic or acquired resistance to the drug. Our preliminary data indicate that CXs inhibit growth of GC-resistant PDA tumorsand also have a synergistic effect with GC against PDA. In this Aim, we will further explore the possibility of using CXs to treat GC-resistant PDA tumors using CX-X alone or in combination with GC against a larger number of patient tumor samples grown in mice. 3. To assess tumor expression of the FACT subunit SSRP1 as a potential marker of sensitivity to CX treatment and to develop a pharmacodynamic assay based on this. SSRP1 is expressed at a high level in many types of tumors (including PDA), but isundetectable in most normal tissues (Preliminary data). In the proposed studies, we will analyze protein and RNA level of both FACT subunits in PDA samples used for the treatment with CX in aim 2. In addition, we will assess the level of total and free soluble SSRP1 (sSSRP1) in tumor samples obtained from aim 2 in vitro and in vivo and to see if the level of total SSRP1 has any correlation with response of tumor to CX treatment (predictive marker) and if the level of sSSRP1 is reduced in response to CX treatment (pharmacodynamic marker). Successful completion of this aim will likely provide valuable markers for use in clinical trials. PUBLIC HEALTH RELEVANCE: This project is devoted to the development of a new type of treatment of one of the mostaggressive types of cancer pancreatic ductal adenocarcinoma (PDA). Treatment options for patients with PDA are currently very limited and prognosis is very poor. We have recently discovered and development new types of anti-cancer agents, named Curaxins (CXs). CXs act through inhibition of Facilitate Chromatin Transcription (FACT) complex, involved in RNA transcription, DNA replication and cell proliferation (mitosis). They also modulate several signaling pathways important for PDA progression. Preliminarydata demonstrated that CXs are toxic for PDA cells in vitro and in vivo and therefore may be proposed as a candidate anti-cancer agent for PDA.

* Information listed above is at the time of submission. *

Agency Micro-sites

SBA logo
Department of Agriculture logo
Department of Commerce logo
Department of Defense logo
Department of Education logo
Department of Energy logo
Department of Health and Human Services logo
Department of Homeland Security logo
Department of Transportation logo
Environmental Protection Agency logo
National Aeronautics and Space Administration logo
National Science Foundation logo
US Flag An Official Website of the United States Government