Sunday, May 11, 2025
5/11/2025
FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers - Defects in DNA damage response (DDR) is major factor that predispose normal cells to acquire oncogenic mutations. However, after a tumor develops, cancer cells manage their survival by repairing DNA damage resulting from unchecked DNA replication. Cancer cells can use the alternative or backup DNA repair programs to overcome their DDR defects. For example, cancer cells with deficiency in homologous recombination (HR) proteins (such as BRCA1) can repair their DNA by either relying on other highly expressed HR-related proteins (such as RAD51 or PARP1) or by using other DNA repair mechanisms such as alternative non-homologous end joining (ALT NHEJ) and basal excision repair (BER). The addiction of cancer cells to these rescue DNA repair pathways contributes to therapy-resistance; therefore, successful targeting of factor(s) that play critical role in multiple DNA repair pathways will have promising clinical outcomes. Alterations in DNA repair pathways commonly occur during breast cancer (BC) progression. For example, triple negative breast cancer (TNBC) an aggressive BC subtype that frequently relapses as distant metastases, have dysfunctional BRCA1 but expresses high levels of RAD51. Further, estrogen receptor positive BC (ER+BC), which accounts for ~70% of all BCs, employs ALT NHEJ, HR or BER to repair their DNA. Notably, ER+BCs acquire resistance to endocrine therapy and DNA-damaging chemotherapy drugs by inducing expression of DNA repair genes. A key factor that is involved in regulating multiple DNA repair pathways is FOXM1, which is highly expressed in TNBC and therapy resistant ER+BCs. FOXM1 is known to promote resistance to chemotherapy drugs and anti-estrogen therapies. In this proposal, we provide compelling evidence that imipramine blue (IB), a novel analogue of anti-depressant imipramine that we recently synthesized inhibits FOXM1-associated signaling impeding DNA repair ability of TNBCs and ER+BC. Using tumor explants from BC patients and tumor xenograft models, we have demonstrated that IB inhibits the growth of TNBC and ER+BC without inducing any toxicity. Further, our studies have shown that IB may sensitize endocrine resistant ER+BCs to tamoxifen (TAM) and improve the efficacy of DNA damaging chemotherapy drugs in TNBC. Based on these observations, we hypothesize that FOXM1 is a critical component of rescue DNA repair pathways that BCs get addicted to survive; that IB suppresses ER+BC and TNBC growth and progression as well as enhances the therapy response by targeting FOXM1 and its associated signaling; and that IB is a safe and effective drug for treating ER+BC and TNBC. In Aim 1, we will characterize the IB-target protein interaction and determine the mechanism(s) by which IB regulates its target genes in TNBC and ER+BC. In Aim 2, we will test the hypothesis that IB inhibits TNBC and ER+BCs growth, metastasis, and enhances therapy response by inhibiting backup DNA repair pathways that these cancers employ to survive. In Aim 3, we will test the safety and viability of IB by using patient derived xenografts in humanized mice and by using human breast cancer explant studies. We will also establish PK/PD parameters required for future clinical development of IB.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).