Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours

Konstantinopoulos, Panagiotis A.; Cheng, Su–Chun; Supko, Jeffrey G.; Polak, Madeline; Wahner-Hendrickson, Andrea E.; Ivy, S. Percy; Bowes, Brittany; Sawyer, Hannah; Basada, Patrice; Hayes, Martin; Curtis, Jennifer; Horowitz, Neil S.; Wright, Alexi A.; Campos, Susana M.; Ivanova, Elena; Paweletz, Cloud P.; Palakurthi, Sangeetha; Liu, Joyce F.; D’Andrea, Alan D.; Gokhale, Prafulla C.; Chowdhury, Dipanjan; Matulonis, Ursula A.; Shapiro, Geoffrey I.

doi:10.1038/s41416-021-01664-8

Cited by 25 publications

(14 citation statements)

References 41 publications

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“…In combination therapy studies, olaparib has been studied with bevacizumab [ 49 ], cediranib [ 50 , 51 , 52 ], paclitaxel [ 53 , 54 , 55 ], carboplatin [ 56 , 57 , 58 , 59 ], a carboplatin/paclitaxel combination [ 60 , 61 , 62 ], cyclophosphamide [ 63 ], liposomal doxorubicin [ 64 ], cisplatin [ 65 ], lurbinectedin [ 66 ], durvalumab [ 51 , 52 , 67 ], dacarbazine [ 68 ], eribulin [ 69 ], ceralasertib [ 70 ], onalespib [ 71 ], prexasertib [ 72 ], gemcitabine [ 73 ], a cisplatin/gemcitabine combination [ 74 ], topotecan [ 75 ], and radiation therapy [ 76 ]. Olaparib was also studied in combination with phosphatidylinositol 3-kinase (PI3K) inhibitors (PI3Ki).…”

Section: Olaparibmentioning

confidence: 99%

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

Menezes

Raheem

Mina

et al. 2022

Cancers

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Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

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Section: Olaparibmentioning

confidence: 99%

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

Menezes

Raheem

Mina

et al. 2022

Cancers

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“…In the subsequent phase I clinical study, a total of 28 patients with advanced solid cancer were enrolled, of which two patients with BRCA-mutated HGSOC who had previously received Olaparib and onalespib therapy had stable disease after 24 weeks of treatment. Overall, 68% of patients had stable disease, 32% had progressive disease, and 32% experienced clinical benefit from the regimen ( Konstantinopoulos et al, 2022 ). At present, the HSP90 inhibitor TAS-116 (pimitespib) has achieved great results in the treatment of gastric stromal tumors, significantly prolonged PFS compared to the original treatment ( Doi et al, 2019 ; Saito et al, 2020 ).…”

Section: Overcoming Resistance To Parpimentioning

confidence: 99%

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

Wang

Yan²,

Da³

et al. 2022

Front. Pharmacol.

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Breast cancer and gynecological tumors seriously endanger women’s physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

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“…In addition, mutations and/or the reduction in PARP1 protein expression can drive resistance to PARP inhibitor therapy [221], while the stabilization of BRCA1 isoforms is also a driver of PARP inhibition resistance. In this context, an HSP90-dependent mechanism has been described, leading to the investigation of HSP90 inhibition as a novel approach to restoring PARP inhibitor sensitivity in this context [222,223]. It will be interesting to see in the coming years, the frequency with which resistance mechanisms seen in preclinical models appear in the clinic.…”

Section: Acquired Parp Inhibitor Resistancementioning

confidence: 99%

DNA repair as a shared hallmark in cancer and ageing

Clarke

Mostoslavsky

2022

Molecular Oncology

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Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well‐orchestrated DNA repair pathways to respond to and resolve many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development. Understanding the fundamental mechanisms of DNA repair will help develop novel strategies to treat ageing‐related diseases. Here, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease. We discuss the use of PARP inhibitors in the clinic for the treatment of breast and ovarian cancer and the challenges associated with acquired drug resistance. Finally, we discuss how DNA repair pathway‐targeted therapeutics are moving beyond PARP inhibition in the search for ever more innovative and efficacious cancer therapies.

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Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours

Cited by 25 publications

References 41 publications

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

DNA repair as a shared hallmark in cancer and ageing

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