PARP Inhibitors: The Journey From Research Hypothesis to Clinical Approval

Kishan AT Naipal; Dik C van Gent

Personalized Medicine. 2015;12(2):139-154.

Sensitizing Tumors for PARP Inhibitors

The number of HR-deficient tumors that would benefit from PARP inhibitor treatment is relatively low, at this moment primarily the BRCA mutated breast and ovarian tumors. However, the utility of these inhibitors may be increased drastically if one could generate an HR-deficient state in tumor cells. One possible way of achieving this is by applying hyperthermia, an increase of temperature above 37°C. This treatment sensitizes cells to radiotherapy and is being validated in clinical setting now.^[82,83] The mechanism depends in part on inhibition of DSB repair, especially HR.^[84,85] This hyperthermia induced HR-deficiency is thought to be the result of proteasomal degradation of BRCA2, which also sensitizes tumor cells to PARP inhibitors.^[86] Obviously, this strategy can only be applied to solid tumors that are easily accessible for hyperthermia treatment. The optimization of hyperthermia techniques to achieve effective heating of solid tumor areas is ongoing and holds great promise.^[87] Furthermore, the use of PARP inhibitors instead of, or in combination with, radiation therapy after hyperthermia is under investigation and can be expected to boost the effectiveness of PARP inhibitors, also for treatment of HR-proficient tumors.

Another recent discovery claims that histone deacetylase inhibitors (HDACi) increase the sensitivity of certain tumor cells to PARP inhibitors.^[88,89] These research groups have shown that the treatment with HDACi downregulates gene expression of BRCA1, BRCA2, ATR and CHK1. Furthermore, functionally the formation of RAD51 foci in response to DNA damage is reduced in HDACi treated cells suggesting an induced HR deficiency. PARP inhibitor treatment after prior HDACi treatment induced significantly more ?H2AX foci and resulted in more cell death in several ovarian cancer cell lines and triple negative breast cancer cell lines.^[88,89] Thus, HDACi treatment might also sensitize HR-proficient tumors to PARP inhibitors; however, the clinical significance and exact mechanism of this are still under investigation. Importantly, it has not been investigated whether normal tissue, for example, intestinal mucosal lining and hematopoietic cells, are also sensitized by HDACi. This is crucial to predict adverse effects of this treatment.

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Abstract
Cancer Epidemiology & Therapy
Genetic Concepts for Targeted Cancer Treatment
Targeting the DDR in Cancer
PARP Inhibitors Target the DDR
PARP Inhibitors in the Clinic
Clinical PARP Inhibitors: Where Are We Now?
Predictive Biomarkers for PARP Inhibitor Sensitivity
Sensitizing Tumors for PARP Inhibitors
Resistance Mechanisms
Conclusion
Future Perspective
References
Sidebar

Table 1. Poly-(ADP-ribose) polymerase inhibitors in clinical studies.
PARP inhibitor	Number of completed or ongoing studies	Type of studies completed or ongoing	Specific tissue cancers that were studied	Combination therapy studied
Olaparib (AZD2281)	52	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine and peritoneal), prostate, gastric, pancreatic, head and neck, lung and colorectal carcinoma; Solid metastatic tumors; Ewings sarcoma; Melanoma	Paclitaxel, Carbo/Cis-platin, Cetuximab, Bevecizumab, Irinotecan, Topotecan, Decarbazine, Doxorubicin, Gemcitabine, Temozolamide
Rucaparib (AGO14699)	7	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine and peritoneal) and pancreatic carcinoma; Solid metastatic tumors; Melanoma	Carboplatin, Cisplatin
Veliparib (ABT-888)	73	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine, cervical and peritoneal), prostate, pancreatic, head and neck, lung, urothelial, biliary, liver and colorectal carcinoma; Solid metastatic tumors; Melanoma; Childhood gliomas and glioblastomas; Lymphomas, Multiple myeloma and Leukemia	Paclitaxel, Carbo/Cis/Oxali-platin, Cetuximab, Rituximab, Bevecizumab, Irinotecan, Topotecan, Decarbazine, Doxorubicin, Gemcitabine, Capecitabine, Temozolamide, Etoposide, Bendamustine, Dinaciclib, MitomycinC, Cyclophosphamide, Floxuridine, Bortezomib
Niraparib (MK4827)	3	Phase I and III	Breast and ovarian carcinoma; Ewings sarcoma	Temozolamide
BMN-673	9	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine and peritoneal), prostate, pancreatic and lung carcinoma; Solid metastatic tumors; Ewings sarcoma; Leukemia	Temozolamide

PARP:Poly-(ADP-ribose) polymerase.
Data taken from [22].

Table 2. Poly-(ADP-ribose) polymerase inhibitors currently in Phase III trials.
PARP inhibitor	Phase III trials (registration number)	Condition	Combination therapy	Randomized	Double blind
Olaparib (AZD2281)	1. NCT02000622	Metastatic breast cancer	Olaparib monotherapy	Yes	No
	2. NCT02032823	Germline BRCA1/2 mutated and high-risk HER2-negative primary breast cancer who have completed definitive local treatment and neo-adjuvant or adjuvant chemotherapy	Olaparib monotherapy	No	No
	3. NCT01874353	Platinum Sensitive BRCA Mutated Relapsed Ovarian Cancer Following Complete or Partial Response to Platinum-Based Chemotherapy	Olaparib monotherapy	Yes	Yes
	4. NCT01844986	Newly Diagnosed Advanced Ovarian Cancer with BRCA Mutation and Complete or Partial Response to First Line Platinum Chemotherapy	Olaparib monotherapy	Yes	Yes
	5. NCT01924533	Advanced Gastric cancers that have progressed during first line chemotherapy	Olaparib + Paclitaxel	Yes	Yes
Rucaparib (AGO14699)	1. NCT01968213	Ovarian Cancer, Fallopian Tube Cancer and Peritoneal Cancer stratified by gene mutation status	Rucaparib monotherapy	Yes	Yes
Veliparib (ABT-888)	1. NCT02032277	Early stage Triple Negative Breast Cancer.	Veliparib + Carboplatin (neo-adjuvant therapy)	Yes
Niraparib (MK4827)	1. NCT01847274	Platinum sensitive ovarian cancer	Niraparib monotherapy	Yes	Yes
	2. NCT01905592	Advanced metastatic breast cancer with germline BRCA1/2 mutation	Niraparib monotherapy	Yes	No
BMN-673	1. NCT01945775	Breast Neoplasms with germline BRCA 1/2 mutation	BMN-673 monotherapy	Yes	No

PARP: Poly-(ADP-ribose) polymerase.
Data taken from [22].

Sidebar

Executive Summary

Cancer epidemiology & therapy

Healthcare systems will be burdened with increasing numbers of cancer patients in the near future. Therefore, optimization of current treatment strategies and development of new strategies, such as targeted therapies, are needed to sustain our healthcare system.

Genetic concepts for targeted cancer treatment

Two different concepts for targeted treatment are currently used: oncogene addiction and synthetic lethality. Synthetic lethality can be achieved when tumor cells have sustained mutations that inactivate one pathway, thereby making the tumor dependent on a compensatory pathway. Inhibition of this compensatory pathway can then kill tumor cells without harming normal cells.

Targeting the DNA damage response

Genetic instability caused by DNA damage response (DDR) defects is frequently observed in tumors. DDR defects not only predispose to cancer, but also provide targets for therapy as a form of personalized medicine.

PARP inhibitors target the DDR

PARP enzymes support single strand break repair and prevent formation of DNA double strand breaks (DSBs) during replication. Repair of these DSBs requires homologous recombinaion (HR) for efficient repair, a process which is defective in hereditary breast cancer caused by inactivation of the BRCA1 or BRCA2 gene. Therefore, PARP inhibition kills these HR-deficient tumor cells without killing normal cells, which still retain an intact copy of the gene.

PARP inhibitors in the clinic

Poly-(ADP-ribose) polymerase (PARP) inhibitors have shown strong potential during early clinical development. Currently, five PARP inhibitor drugs are running in clinical trials for approval. All have shown proof of concept success in germline BRCA mutation carriers. Furthermore, several combinations with other drugs are being investigated.

Clinical PARP inhibitors: where are we now?

All PARP inhibitors are running in Phase III clinical trials for approval. Inclusion criteria are germline BRCA1 or BRCA2 mutations or ovarian cancer patients having successfully completed platinum-based chemotherapy. In two Phase III trials the chemo potentiating effect of PARP inhibitors on other drugs is being investigated.

Predictive biomarkers for PARP inhibitor sensitivity

Current patient selection is based on germline BRCA1 and BRCA2 status. Furthermore, many single-gene predictive biomarkers for PARP inhibitor response have been identified in a research setting, which may help to increase the number of eligible patients. Other promising approaches to identify PARP inhibitor sensitive tumors are functional ex vivo assays and identification of specific signatures using massive omics techniques. All approaches still need validation in prospective clinical studies.

Sensitizing tumors for PARP inhibitors

The recent observation that HR can be downregulated by hyperthermia treatment holds great promise for sensitizing even HR-proficient tumors to PARP inhibitors.

Resistance mechanisms

PARP inhibitor treatment can induce various resistance mechanisms, including re-activating BRCA mutations, mutations in HR-inhibiting genes and upregulation of drug efflux pumps. Clinical relevance of these mechanisms remains to be confirmed.

Conclusion

PARP inhibitors are expected be approved for specific tumors soon. However, biomarker discovery should be maintained to increase the number of patients that may benefit from the treatment. Also emerging resistance should be closely monitored and methods to counter this resistance should be developed.