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Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy.

ABSTRACT: Chemoradiation is an effective combined modality therapeutic approach that utilizes principles of spatial cooperation to combat the adaptability associated with cancer and to potentially expand the therapeutic window. Optimal therapeutic efficacy requires intelligent selection and refinement of radiosynergistic pharmaceutical agents, enhanced delivery methods, and temporal consideration. Here, a monodisperse sub-20 nm mixed poloxamer micelle (MPM) system was developed to deliver hydrophobic drugs intravenously, in tandem with ionizing radiation. This report demonstrates in vitro synergy and enhanced radiosensitivity when two molecularly targeted DNA repair inhibitors, talazoparib and buparlisib, are encapsulated and combined with radiation in a 4T1 murine breast cancer model. Evaluation of in vivo biodistribution and toxicity exhibited no reduction in particle accumulation upon radiation and a lack of both acute and chronic toxicities. In vivo efficacy studies suggested the promise of combining talazoparib, buparlisib, and radiation to enhance survival and control tumor growth. Tissue analysis suggests enhanced DNA damage leading to apoptosis, thus increasing efficacy. These findings highlight the challenges associated with utilizing clinically relevant inclusion criteria and treatment protocols because complete tumor regression and extended survival were masked by an aggressively metastasizing model. As with clinical treatment regimens, the findings here establish a need for further optimization of this multimodal platform.

SUBMITTER: DuRoss AN

PROVIDER: S-EPMC7213279 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy.

DuRoss Allison N AN Neufeld Megan J MJ Landry Madeleine R MR Rosch Justin G JG Eaton Colin T CT Sahay Gaurav G Thomas Charles R CR Sun Conroy C

ACS applied materials & interfaces 20190321 13

Chemoradiation is an effective combined modality therapeutic approach that utilizes principles of spatial cooperation to combat the adaptability associated with cancer and to potentially expand the therapeutic window. Optimal therapeutic efficacy requires intelligent selection and refinement of radiosynergistic pharmaceutical agents, enhanced delivery methods, and temporal consideration. Here, a monodisperse sub-20 nm mixed poloxamer micelle (MPM) system was developed to deliver hydrophobic drug ...[more]

PMID: 30860347

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Project description:Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia-telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation.

Project description:BackgroundThe optimal sequencing of chemotherapy and radiotherapy after breast surgery was largely studied but remains controversial. Concurrent chemo-radiotherapy is a valuable method for adjuvant treatment of breast cancer which is under ongoing research program in our hospital. We are evaluating the feasibility of the concomitant use of chemotherapy retrospectively.MethodsTwo hundred forty four women having breast cancer were investigated in a retrospective study. All patients were either treated by radical surgery or breast conservative surgery. The study compares two adjuvant treatments associating concomitant chemotherapy and radiotherapy. In the first group (group A) the patients were treated by chemotherapy and radiotherapy in concomitant way using anthracycline (n = 110). In the second group (group B) the patients were treated by chemotherapy and radiotherapy in concomitant way using CMF treatment (n = 134). Chemotherapy was administered in six cycles, one each 3 weeks. Radiotherapy delivered a radiation dose of 50 Gy on the whole breast (or on the external wall) and/or on the lymphatic region. The Kaplan-Meier method was used to estimate the rates of disease free survival, loco-regional recurrence-free survival and overall survival. The Pearson Khi2 test was used to analyse the homogeneity between the two groups. The log-rank test was used to evaluate the differences between the two groups A and B.ResultsAfter 76.4 months median follow-up (65.3 months mean follow up), only one patient relapsed to loco-regional breast cancer when the treatment was based on anthracycline. However, 8 patients relapsed to loco-regional breast cancer when the treatment was based on CMF. In the anthracycline group, the disease free survival after 5 years, was 80.4% compared to 76.4% in the CMF group (Log-rank test: p = 0.136). The overall survival after 5 years was 82.5% and 81.1% in the anthracycline and CMF groups respectively (Log-rank test: p = 0.428). The loco-regional free survival at 5 years was equal to 98.6% in group A and 94% in group B (Log-rank test: p = 0,033). The rate of grade II and grade III anaemia was 13.9% and 6.7% in anthracycline group and CMF group respectively (Khi2-test: p = 0.009). The rate of grade II and grade III skin dermatitis toxicity was 4.5% in the group A and 0% in the group B (Khi2-test: p = 0.013).ConclusionFrom the 5 years retrospective investigation we showed similar disease free survival and overall survival in the two concurrent chemo-radiotherapy treatments based on anthracycline and CMF. However in the loco-regional breast cancer the treatment based on anthracycline was significantly better than that of the treatment based on CMF. There was more haematological and skin dermatitis toxicity in the anthracycline group.

Dataset Information

Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy.

Publications

Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy.

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