Friday, May 3, 2024
5/3/2024
Cancer cells despite defective DNA damage response (DDR) have unique ability to repair their DNA and continue their DNA replication. The higher rate of DNA replication and heightened DNA repair activity (albeit error-prone) though ensure uncontrolled proliferation but also produce genetic mutations at high frequencies in cancer cells. This alteration of cellular DNA and dependency of cancer cells to incessant replication initially became the justification for targeting DNA as a cancer therapy. Though successful to some extent, the major limitations of DNA targeting drugs that are used in clinics today include life threatening toxicity, acquired resistance and occurrence of secondary cancers. These problems mostly stem from the ability of DNA targeting drugs to indiscriminately bind to cellular DNA or other non-DNA macromolecules resulting in DNA damage. We reason new DNA interacting drugs that (1) display high sequence/region specificity (2) do not directly damage the DNA and (3) target DNA-related processes that tumor cells use but not the normal cells could have favorable therapeutic outcomes. In this proposal, we provide compelling evidence that Carbazole Blue (CB) may be one such drug that we recently developed. We synthesized CB from carbazole, which is an active ingredient of coal tar that is used for the treatment of Psoriasis. Using an unbiased genome-wide approach, we discovered that CB interacts with A/T rich DNA regions. Importantly, using cell lines, patient-derived ex-vivo explants (PDEx), patient-derived organoids (PDO) and xenografts (PDX) as well as orthotopic xenograft models, we found that in contrast to chemotherapy drugs, CB is a potent and safe anti-cancer compound as systemic delivery of CB inhibits growth and progression of TNBC and ER+ breast cancers (BCs) without inducing any toxicity. We discovered that CB inhibits the activity of A/T rich binding protein HMGA1 and consequently expression of several genes including CDK4, MCMs, GINS and CDC6 and that are highly expressed in these BCs and play critical roles in replication and DNA repair. Importantly, HMGA1 and its target proteins are reported to regulate PARP inhibitor (PARPi) and CDK4/6 inhibitor (CDK4/6i) responses in TNBC and metastatic ER+BCs, respectively. Three Specific Aims are proposed: In Aim1, we will test the hypothesis that CB preferentially targets specific domains in the DNA that are critical for cancer cell proliferation/progression to selectively induce cancer cell death. In Aim 2, we will elucidate the mechanisms by which CB utilizes target genes such as HMGA1 to sensitize PARPi and CDK4/6i responses leading to growth/metastasis inhibition of TNBC and ER+BCs, respectively. In Aim 3, we will test the hypothesis that CB serves as a novel, safe and potent anti-tumor agent and therapeutic adjuvant for treating BCs using PDX, PDO and PDEx models. We will also establish PK/PD parameters required for future clinical development of CB. Successful completion of this study will set the stage for a new paradigm of treating BCs using CB as a therapeutic.
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