Development of a new small molecule therapeutic for the treatment of resistant breast cancer

PROJECT SUMMARYABSTRACTBreast cancer is the second leading cause of death in females with cancerInapproximatelynew cases of invasive breast cancer were diagnosedwhere an estimate ofwas expected to succumb to their diseaseIt is estimated that one in eight women will develop breast cancer in their lifetimeBreast cancer is classified into subtypes based on the expression of estrogen receptorERprogesterone receptorPRand amplification of human epidermal growth factor receptorHERThe presence or absence of these molecular markers has been used to estimate clinical prognosis and to determine treatment response to current breast cancer therapies targeting these pathwaysDespite these therapeutic advancesbreast cancer patients that have undetectable ERPR and HERknown as triple negative breast cancerTNBCcannot benefit from these targeted treatmentsCytotoxic chemotherapy continues to be the primary treatment option for TNBC patientswhich typically have poor prognosis and significantly lower overall survival when compared to patients that are ER and or PR positiveThusthere is a major unmet medical need to develop effective long term therapies for resistant breast cancersincluding TNBCResistant tumors are able to survive and thrive in the hostile tumor microenvironment with low nutrients and oxygen by adapting to such toxic milieu through various survival mechanismssuch as sustained unfolded protein responseUPRor persistent endoplasmic reticulum stressERSand autophagyThe hallmark of ERS is the enhanced expression of chaperone proteins that facilitate the clearance of misfolded proteinsand as a result they promote anti apoptotic mechanisms and enhance cancer cell survivalThe overexpression of these chaperone proteins can also confer resistance towards cytotoxic chemotherapyThereforeit is not surprising that tumor cells with chronic low level of ERS are able to survive and even thrive in inhospitable environmentsincluding cytotoxic chemotherapyThis project is supported by our findings that even a small increase in the ER stress levels in tumor cells can surpass a certain threshold where it triggers apoptotic cell death specifically in tumor cellsBased on our investigations of this novel conceptwe identified a lead compoundwhich was shown to have efficacy and safety profile suitable to advance for human evaluationThis small molecule was found to be active in a wide range of cancers includinglungbrainbreastand colon cancersand was shown to be active alone and in combination with conventional chemotherapy in TNBCsThis project will support the advancement of our lead compound towards clinical developmentThis will be accomplished by establishing the optimal dosage and frequency when used alone and in combination with cytotoxic chemotherapyand by determining its pharmacokinetics and pharmacodynamicsThese efforts will set the stage for completing the preclinical studies of this promising compoundand will help advance it towards clinical studies for resistant breast cancersincluding TNBC