Exploiting Senescence for Breast Cancer Prevention and Treat

Institution: The Burnham Institute for Medical Research
Investigator(s): Charles Spruck, Ph.D. -
Award Cycle: 2015 (Cycle 21) Grant #: 21IB-0113 Award: $292,500
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2015)

Non-technical overview of the research topic and relevance to breast cancer: Despite the recent success of “targeted drugs”, traditional chemotherapy, which acts broadly to kill cells, is still the drug of choice for triple-negative breast cancers (TNBCs). However, chemotherapy is highly toxic and causes severe side effects for patents. There is an urgent need in breast cancer treatment to replace interventions with life threatening toxicities with ones that are safe and effective. We have been exploring potentially new therapeutic approaches for TNBC treatment that exploit the “natural” processes present within all cells. Senescence, which is a state of irreversible quiescence, is one such process. In normal breast cells, senescence acts a crucial barrier against cancer development. The activation of oncogenes or inactivation of tumor suppressor genes triggers senescence, which promotes the irreversible growth arrest of pre- malignant cells and their subsequent eradication from the body. In order for breast cancers to fully develop, a premalignant breast cell must somehow acquire the ability to overcome the senescence barrier and then maintain an anti-senescent state. However, very little is known about how these processes are controlled. In our preliminary studies, we sought to identify the genes that are required for breast cancer cells to maintain an anti-senescent state. We used an innovative cell image-based functional screening approach and identified a largely uncharacterized enzyme called Fbxo44 as a crucial determinant in this process. Knockdown of Fbxo44 expression in all breast cancer cell lines tested, including TNBCs and the aggressive chemotherapy resistant claudin-low TNBC sub-type, induced profound irreversible senescence, suggesting that breast cancer cells are “addicted” to Fbxo44 for their continued growth. Importantly, we found that Fbxo44 inhibition was even capable of inducing senescence in TNBC cells deficient in p53, pRb, or BRCA1, which are the major senescence regulations in breast cells and important determinants of TNBC aggressiveness. Our additional studies showed that Fbxo44 might function by regulating key enzymes involved in DNA synthesis and chromatin epigenetics; processes intricately linked with cellular senescence.

The question(s) or central hypotheses of the research: Targeted inhibition of Fbxo44 could be a powerful therapeutic approach for eradicating TNBCs through the novel mechanism of induced cellular senescence. Because Fbxo44 functions independent of p53, pRb, and BRCA1, this “pro- senescence” therapy could be effective against even the most aggressive TNBCs, including claudin-low cancers which are generally resistant to chemotherapy. In addition, Fbxo44 targeted inhibitors are expected to display significantly reduced toxicity compared to conventional chemotherapy since they exploit a natural process common to all cells in the body.

 The general methodology: We will use molecular and biochemical approaches to elucidate the molecular mechanism(s) by which Fbxo44 inhibition promotes senescence of TNBC cells. This will include an examination of Fbxo44’s putative role in controlling chromatin modifications. We will also evaluate the effects of Fbxo44 inhibition on inducing senescence of TNBC stem cell/tumor-initiating cells (TICs). Finally, we will use a mouse breast cancer model to evaluate the therapeutic potential of Fbxo44 inhibitors in preventing the growth of TNBC stem/TICs in vivo and tumorigenicity of chemotherapy resistant claudin-low TNBCs, through the mechanism of induced senescence.

Innovative elements of the project: 1) The concept of exploiting the senescence program for breast cancer/TNBC treatment is highly novel and no current cancer drug is known to function via this mechanism; 2) Fbxo44 represents the only senescence pathway identified to date that functions independent of the crucial senescence effectors p53, pRb, and BRCA1, suggesting that cancers defective in these genes will be susceptible to Fbxo44-targeted inhibition; and 3) Since stem/TICs are susceptible to senescence, Fbxo44 inhibition offers a potentially highly effective therapeutic approach for eradicating the cancer stem/TIC component of TNBCs, thereby preventing these cancers from recurring and/or metastasizing, for which no other therapy has been shown effective.

Publications:
F-box proteins in epigenetic regulation of cancer



F-Box Proteins in Epigenetic Regulation of Cancer https://www.jscimedcentral.com/CancerBiology/cancerbiology-4-1088.pdf
Periodical:Journal of Cancer Biology and Research
Index Medicus: J Cancer Biol Res
Authors: Shen, J and Spruck C
Yr: 2016 Vol: 4 Nbr: 3 Abs: Pg:1088