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.