PARP inhibitor and chemotherapy combination trials for the treatment of advanced malignancies: does a development pathway forward exist?

Matulonis, Ursula A.; Monk, Bradley J.

doi:10.1093/annonc/mdw697

Cited by 51 publications

(36 citation statements)

References 23 publications

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“…Our 3D tumor-on-a-chip results were consistent with the results from studies testing PARP1 inhibitors in combination with chemotherapy in breast cancer trials, 11 and consistent with results from another in vitro study targeting ovarian cancer. 35 Many TNBC studies have shown that the combinations do not provide benefit beyond the standard of care.…”

supporting

confidence: 87%

“…8 Typically, the double-stranded DNA breaks would be repaired through either the HR or NHEJ pathway. 11 The combinational therapeutic success may be mediated by several variables including: the type of PARP1 inhibitor, the pharmacokinetic properties of the combinational chemotherapeutic drugs, the suboptimal dosage, and the patients' genetic profiles. The error-prone NHEJ repair pathway predominates, culminating in genomic instability, and ultimately cell death.…”

mentioning

confidence: 99%

“…10 Studies of PARP1 inhibition in conjunction with chemotherapy have consequently been tested in clinical trials as a means to improve the therapeutic efficacy, but similarly, limited improvement was found. 11 The combinational therapeutic success may be mediated by several variables including: the type of PARP1 inhibitor, the pharmacokinetic properties of the combinational chemotherapeutic drugs, the suboptimal dosage, and the patients' genetic profiles. While the genetic synthetic lethality paradigm may hold therapeutic promise for TNBC, combining PARP1 inhibitor drugs with chemotherapy to take advantage of this genetic relationship may be more challenging than anticipated.…”

mentioning

confidence: 99%

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CRISPR/Cas9‐mediated mutagenesis to validate the synergy between PARP1 inhibition and chemotherapy in BRCA1‐mutated breast cancer cells

Mintz

Lao

Chi

et al. 2020

Bioengineering & Transla Med

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For patients carrying BRCA1 mutations, at least one-third develop triple negative breast cancer (TNBC). Not only is TNBC difficult to treat due to the lack of molecular target receptors, but BRCA1 mutations (BRCA1m) also result in chemotherapeutic resistance, making disease recurrence more likely. Although BRCA1m are highly heterogeneous and therefore difficult to target, BRCA1 gene's synthetic lethal pair, PARP1, is conserved in BRCA1m cancer cells. Therefore, we hypothesize that targeting PARP1 might be a fruitful direction to sensitize BRCA1m cancer cells to chemotherapy. We used CRISPR/Cas9 technology to generate PARP1 deficiency in two TNBC cell lines, MDA-MB-231 (BRCA1 wild-type) and MDA-MB-436 (BRCA1m). We explored whether this PARP1 disruption (PARP1m) could significantly lower the chemotherapeutic dose necessary to achieve therapeutic efficacy in both a 2D and 3D tumor-on-a-chip model. With both BRCA1m and PARP1m, the TNBC cells were more sensitive to three representative chemotherapeutic breast cancer drugs, doxorubicin, gemcitabine and docetaxel, compared with the PARP1 wild-type counterpart in the 2D culture environment. However, PARP1m did not result in this synergy in the 3D tumor-on-a-chip model, suggesting that drug dosing in the tumor microenvironment may influence the synergy. Taken together, our results highlight a discrepancy in the efficacy of the combination of PARP1 inhibition and chemotherapy for TNBC treatment, which should be clarified to justify further clinical testing. K E Y W O R D S BRCA1, CRISPR/Cas9, PARP1, precision medicine, synthetic lethality, triple negative breast cancer Breast cancer is the leading cause of death in women worldwide. 1Around 12-17% of breast cancer patients have triple negative breast cancer (TNBC), 2 an aggressive, heterogeneous subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor Type 2 (HER2) expression.

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confidence: 87%

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confidence: 99%

mentioning

confidence: 99%

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CRISPR/Cas9‐mediated mutagenesis to validate the synergy between PARP1 inhibition and chemotherapy in BRCA1‐mutated breast cancer cells

Mintz

Lao

Chi

et al. 2020

Bioengineering & Transla Med

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“…A major barrier to combining PARP inhibitors with chemotherapy is a frequent inability to achieve full doses of both regimens secondary to overlapping myelosuppressive toxicities [Matulonis and Monk, 2017]. Phase I and single-arm nonrandomized phase II studies of combined PARP inhibitors and chemotherapy have been reviewed elsewhere [Liu et al 2014b;Miller and Ledermann, 2016].…”

Section: Veliparibmentioning

confidence: 99%

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Evans

Matulonis

2017

Ther Adv Med Oncol

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Abstract:Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy.

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“…However, the combination of gemcitabine, doxorubicin, and taxan showed no significant synergies [64,65]. It was observed that the efficacy of combination therapy with the same chemoagent was dependent on PARP inhibitors [66]. PARP inhibitors are thought to have different synergies in combinations with different chemoagents, depending on the mechanism and activity of cytotoxicity, as well as the regulation of PARylation.…”

Section: Combination Effect Of Conventional Chemotherapy According Tomentioning

confidence: 99%

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Min

2020

Cancers

106

105

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Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation.Cancers 2020, 12, 394 2 of 16 be true, PARP inhibitors that inhibit DDR resulted in improved clinical benefits and became standard therapy [9][10][11]. To date, four PARP inhibitors have been approved by the FDA and are being applied clinically. However, while all PARP inhibitors inhibit PARP catalytic activities, they have different cytotoxicities. Therefore, the anti-tumor effects of the PARP inhibitors have been suggested to be due to PARP trapping, as well as the inhibition of the enzymatic activities [12,13].The catalytic inhibition and trapping effects of PARP are tightly regulated, and the cytotoxicity of each mechanism can cause different reactivities. Therefore, in this review, based on mechanisms of PARP, we intend to examine the difference of anti-tumor effect of the PARP inhibitors and the current aspect of the roles in combination treatment. PARPs and PARylationPoly (ADP-ribose) polymerase (PARP) is a family of 17 proteins in mammals, encoded by different genes, but with a conserved catalytic domain. Other than the catalytic domain, PARP family members contain one or more other motifs or domains, including zinc fingers, a breast cancer-susceptibility protein (BRCA) C-terminus-like (BRCT) motifs, ankyrin repeats, macro domains, and WWE domains [14] ( Figure 1A). PARP1 was the first family member identified and has a critical role in SSB repair through the metabolism of recruiting and dissociating repair proteins by PARylation. In addition to DNA damage repair, PARP1 has important roles in a various range of cellular processes from cell proliferation to cell death, due to having diverse substrates like nuclear proteins involved in transcriptional regulation, apoptotic cell death, chromatin decondensation, inflammation, and cell cycle regulation [15,16]. PARP1 has a total molecular weight of 113 kDa and contains seven independent domains ( Figure 1B) [5,17]. The N-terminus is the DNA binding domain (residues 1-353), which contains three zinc-finger DNA-binding domains, ZnFI, ZnFII, and ZnFIII, which are responsible for recognizing sites of damaged DNA and binding through allosteric activation. ...

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PARP inhibitor and chemotherapy combination trials for the treatment of advanced malignancies: does a development pathway forward exist?

Cited by 51 publications

References 23 publications

CRISPR/Cas9‐mediated mutagenesis to validate the synergy between PARP1 inhibition and chemotherapy in BRCA1‐mutated breast cancer cells

CRISPR/Cas9‐mediated mutagenesis to validate the synergy between PARP1 inhibition and chemotherapy in BRCA1‐mutated breast cancer cells

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

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