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Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy.

ABSTRACT: Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.

SUBMITTER: Landry MR

PROVIDER: S-EPMC7689338 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy.

Landry M R MR DuRoss A N AN Neufeld M J MJ Hahn L L Sahay G G Luxenhofer R R Sun C C

Materials today. Bio 20200901

Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-1 ...[more]

PMID: 33294836

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Project description:Exposure to genotoxic agents, such as irradiation produces DNA damage, the toxicity of which is augmented when the DNA repair is impaired. Poly (ADP-ribose) polymerase (PARP) inhibitors were found to be "synthetic lethal" in cells deficient in BRCA1 and BRCA2 that impair homologous recombination. However, since many tumors, including prostate cancer (PCa) rarely have on such mutations, there is considerable interest in finding alternative determinants of PARP inhibitor sensitivity. We evaluated the effectiveness of radiation in combination with the PARP inhibitor, rucaparib in PCa cells. The combination index for clonogenic survival following radiation and rucaparib treatments revealed synergistic interactions in a panel of PCa cell lines, being strongest for LNCaP and VCaP cells that express ETS gene fusion proteins. These findings correlated with synergistic interactions for senescence activation, as indicated by ?--galactosidase staining. Absence of PTEN and presence of ETS gene fusion thus facilitated activation of senescence, which contributed to decreased clonogenic survival. Increased radiosensitivity in the presence of rucaparib was associated with persistent DNA breaks, as determined by ?-H2AX, p53BP1, and Rad51 foci. VCaP cells, which harbor the TMPRSS2-ERG gene fusion and PC3 cells that stably express a similar construct (fusion III) showed enhanced sensitivity towards rucaparib, which, in turn, increased the radiation response to a similar extent as the DNA-PKcs inhibitor NU7441. Rucaparib radiosensitized PCa cells, with a clear benefit of low dose-rate radiation (LDR) administered over a longer period of time that caused enhanced DNA damage. LDR mimicking brachytherapy, which is used successfully in the clinic, was most effective when combined with rucaparib by inducing persistent DNA damage and senescence, leading to decreased clonogenic survival. This combination was most effective in the presence of the TMPRSS2-ERG and in the absence of PTEN, indicating clinical potential for brachytherapy in patients with intermediate and high risk PCa.

Project description:Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options. We previously found that PARP is overexpressed in SCLC and that targeting PARP reduces cell line and tumor growth in preclinical models. However, SCLC cell lines with PI3K/mTOR pathway activation were relatively less sensitive to PARP inhibition. In this study, we investigated the proteomic changes in PI3K/mTOR and other pathways that occur following PAPR inhibition and/or knockdown in vitro and in vivo. Using reverse-phase protein array, we found the proteins most significantly upregulated following treatment with the PARP inhibitors olaparib and rucaparib were in the PI3K/mTOR pathway (p-mTOR, p-AKT, and pS6) (p≤0.02). Furthermore, amongst the most significantly down-regulated proteins were LKB1 and its targets AMPK and TSC, which negatively regulate the PI3K pathway (p≤0.042). Following PARP knockdown in cell lines, phosphorylated mTOR, AKT and S6 were elevated and LKB1 signaling was diminished. Global ATP concentrations increased following PARP inhibition (p≤0.02) leading us to hypothesize that the observed increased PI3K/mTOR pathway activation following PARP inhibition results from decreased ATP usage and a subsequent decrease in stress response signaling via LKB1. Based on these results, we then investigated whether co-targeting with a PARP and PI3K inhibitor (BKM-120) would work better than either single agent alone. A majority of SCLC cell lines were sensitive to BKM-120 at clinically achievable doses, and cMYC expression was the strongest biomarker of response. At clinically achievable doses of talazoparib (the most potent PARP inhibitor in SCLC clinical testing) and BKM-120, an additive effect was observed in vitro. When tested in two SCLC animal models, a greater than additive interaction was seen (p≤0.008). The data presented here suggest that combining PARP and PI3K inhibitors enhances the effect of either agent alone in preclinical models of SCLC, warranting further investigation of such combinations in SCLC patients.

Project description:BackgroundOvarian cancer (OC) is a prevalent malignancy in the female reproductive system, and developing effective targeted therapies for this disease remains challenging. The aim of this study was to use clinically-relevant OC models to evaluate the therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR inhibitor Cediranib Maleate (CM), for the treatment of advanced OC.MethodsOC tumor specimens and cell lines were analyzed to determine HER2 and VEGFR expression by Western blot, immunocytochemistry and immunofluorescence. Moreover, the OC cell lines, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with RC48 and/or CM and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for OC both in vitro and in vivo. Additionally, RNA-Seq was performed to investigate the critical mechanism underlying the combination therapy of RC48 and CM.ResultsOur results demonstrated that RC48 alone effectively targeted and inhibited the growth of HER2-positive OC tumors in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in human OC cell lines, as well as CDX and PDX models. Mechanistically, we observed that the combination treatment inhibited the growth of OC cells involved inducing apoptosis and suppressing cell motility. RNA-seq analysis provided further mechanistic insights and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the PI3K-AKT pathway played a key role in the inhibition of proliferation triggered by combinational treatment of RC48 and CM in OC cells.ConclusionsThese findings provide a preclinical framework supporting the potential of dual targeting HER2 and VEGFR as a promising therapeutic strategy to improve outcomes in patients with OC.

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Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy.

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Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy.

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