Cancer recurrence after tumor eradication by chemotherapy portends poor outcome. Recent data point to persistence of quiescent cancer cells not eliminated by chemotherapy and able to re-generate tumors as the main contributor to tumor relapse. Such cells have been recognized as cancer stem cells (CSCs) and are programmed to self-renew or to differentiate into progenitor cells, generating new tumors. CSCs are characterized by expression of membrane efflux proteins that render them highly chemotherapy resistant. Several markers have been proposed for CSCs' identification, of which activity of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), either alone, or in combination with other proteins, is a robust identifier that has been validated by several groups in different cancer types, including ovarian. Over the past 20 years, our laboratory has developed the biochemical tools to study the functions of aldehyde dehydrogenases in normal physiology and in metabolic disorders. Equipped with unique expertise in this field, we have recently identified highly potent and specific small molecule inhibitors for ALDH1A1 that block the enzyme at nM concentrations. Here we propose to optimize and validate the lead inhibitor for the first time in a cancer model, focusing on inhibiting the functions of ALDH1A1+ ovarian CSCs. We will determine the lead inhibitor's target specificity and its cytotoxic activity in ALDH1A1+ ovarian cancer cells and will measure its anti-cancer activity in an animal model that replicates tumor recurrence after chemotherapy. The application is highly responsive to the current RFA (PA-12-145) seeking to support new and developmental concepts in cancer therapy. Successful completion of our studies will strongly support a novel CSC targeting strategy and will permit transition of this innovative concept to the clinic.
Ovarian cancer has an exceptionally high relapse rate. We hypothesize that the cancer stem cells responsible for relapse express high levels of an enzyme named aldehyde dehydrogenase 1A1 (ALDH1A1). We propose that treatment with our ALDH1A1 selective inhibitor, A37, will effectively eliminate these tumorigenic and chemotherapy resistant ovarian cancer stem cells and open a new treatment strategy for this deadly cancer.
|Sarvi, Sana; Crispin, Richard; Lu, Yuting et al. (2018) ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. Cell Chem Biol 25:1456-1469.e6|
|Buchman, Cameron D; Hurley, Thomas D (2017) Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives. J Med Chem 60:2439-2455|
|Li, Junjie; Condello, Salvatore; Thomes-Pepin, Jessica et al. (2017) Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell 20:303-314.e5|