Background: Hsp70, a molecular chaperone responsible, in part, for the folding of nascent peptides following translation, has been implicated as a survival factor and a poor prognostic marker in cancer cells. These pro-cancer mechanisms originate in the ability of Hsp70 to preserve and maintain oncogenic and transformative proteins responsible for the cancer phenotype. Hsp70 is a stress response protein such that expression increases under proteomic/proteotoxic stress events. This increased expression is also evident in cancer cells, an environment under proteomic stress brought on by transformation, and is known to be protective against programmed cell death.

Hypothesis: We predict that by interrupting the chaperoning capacity of Hsp70 through allosteric inhibition, we can destabilize oncogenic proteins dependent on Hsp70 for structure and function. Additionally, as Hsp70 is a survival factor, we believe that a loss of Hsp70 activity will result in cancer specific cell death both in vitro and in vivo.

Approach: Using chemical tools, primarily novel allosteric Hsp70 inhibiting small molecules, we will determine the fate of oncogenic proteins dependent on Hsp70 for stability. We will also examine the cellular response to the disruption of cancer-specific networks which require Hsp70. In vivo tumor models will be used to examine the pharmacokinetics and pharmacodynamics of small molecule Hsp70 inhibitors and to evaluate the therapeutic potential of Hsp70 inhibition.

Significance: The stress response machinery is responsible for the stability of proteins, maintenance of signaling pathways, and evasion from programmed cell death while a cell is under stress; stressors including oncogenic transformation. These pathways maintained by the molecular chaperones have been directly linked to deleterious cancer phenotypes including aggressiveness and the emergence of therapeutic resistances. Targeted therapeutics, and uniquely those targeting the molecular chaperone system, can provide therapeutic options capable of ablating the specific mechanisms involved in proteomic stability and cell survival unique to each tumor cell; effects which can be delivered with minimal effect to normal tissue. This work highlights the potential for therapeutics targeting Hsp70 as anti-cancer agents.

Citation Format: John Koren, Chao Xu, Anna Rodina, Liza Shrestha, Tony Taldone, Gabriela Chiosis. Allosteric Hsp70-family inhibitors as targeted anticancer therapeutics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1740. doi:10.1158/1538-7445.AM2015-1740

©2015 American Association for Cancer Research.
2015