Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations
PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatmen...
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| Veröffentlicht in: | Gynecologic oncology 2020-02, Vol.156 (2), p.488-497 |
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| creator | Veneris, Jennifer Taylor Matulonis, Ursula A. Liu, Joyce F. Konstantinopoulos, Panagiotis A. |
| description | PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP inhibitor combinations.
•PARP inhibitors (PARPi) have transformed the management of advanced ovarian cancer.•With increased PARPi use, the resistance to PARPi will become a increasing clinical concern.•Combinatorial approaches can overcome de novo and acquired resistance to PARPi by exploiting DDR mechanisms.•PARPi combinations can induce “BRCAness”, inhibit DNA repair, promote replication stress, or enhance immunomodulation.•Selection of the appropriate combination for the clinical context could overcome, or prevent, PARPi resistance. |
| doi_str_mv | 10.1016/j.ygyno.2019.09.021 |
| format | Article |
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•PARP inhibitors (PARPi) have transformed the management of advanced ovarian cancer.•With increased PARPi use, the resistance to PARPi will become a increasing clinical concern.•Combinatorial approaches can overcome de novo and acquired resistance to PARPi by exploiting DDR mechanisms.•PARPi combinations can induce “BRCAness”, inhibit DNA repair, promote replication stress, or enhance immunomodulation.•Selection of the appropriate combination for the clinical context could overcome, or prevent, PARPi resistance.</description><identifier>ISSN: 0090-8258</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2019.09.021</identifier><identifier>PMID: 31630846</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; BRCA1 Protein - genetics ; BRCA2 Protein - genetics ; Developmental therapeutics ; DNA damage repair ; DNA Repair ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Germ-Line Mutation ; Humans ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - immunology ; PARP inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage ; Randomized Controlled Trials as Topic</subject><ispartof>Gynecologic oncology, 2020-02, Vol.156 (2), p.488-497</ispartof><rights>2019 The Authors</rights><rights>Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-460a1aab828b2964a9dcb15fc2191627f639ddad6d8058e694520ec5536ddf473</citedby><cites>FETCH-LOGICAL-c470t-460a1aab828b2964a9dcb15fc2191627f639ddad6d8058e694520ec5536ddf473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ygyno.2019.09.021$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31630846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Veneris, Jennifer Taylor</creatorcontrib><creatorcontrib>Matulonis, Ursula A.</creatorcontrib><creatorcontrib>Liu, Joyce F.</creatorcontrib><creatorcontrib>Konstantinopoulos, Panagiotis A.</creatorcontrib><title>Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP inhibitor combinations.
•PARP inhibitors (PARPi) have transformed the management of advanced ovarian cancer.•With increased PARPi use, the resistance to PARPi will become a increasing clinical concern.•Combinatorial approaches can overcome de novo and acquired resistance to PARPi by exploiting DDR mechanisms.•PARPi combinations can induce “BRCAness”, inhibit DNA repair, promote replication stress, or enhance immunomodulation.•Selection of the appropriate combination for the clinical context could overcome, or prevent, PARPi resistance.</description><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA2 Protein - genetics</subject><subject>Developmental therapeutics</subject><subject>DNA damage repair</subject><subject>DNA Repair</subject><subject>Female</subject><subject>Genes, BRCA1</subject><subject>Genes, BRCA2</subject><subject>Germ-Line Mutation</subject><subject>Humans</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - immunology</subject><subject>PARP inhibitors</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage</subject><subject>Randomized Controlled Trials as Topic</subject><issn>0090-8258</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN9rFDEQx4Mo9mz9CwTJoy97TrK7uY3gw_XwR6FgafU5ZJPZNsduciZZZf97c171sTAQGD7fmcmHkDcM1gyYeL9fL_eLD2sOTK6hFGfPyIqBbCvRtfI5WQFIqDredmfkVUp7AKiB8ZfkrGaihq4RK5J2DyEk5-_pb5dwXD7QOxzR5GPnZnt7Q51_cL3LIVITpt55nV3wieZADzFMISPVPrsqz1NB3DTNHmnEdCgQJtrjEryll7e7LZ3mfApfkBeDHhO-fnzPyY_Pn77vvlbX375c7bbXlWk2kKtGgGZa9x3vei5Fo6U1PWsHw5lkgm8GUUtrtRW2g7ZDIZuWA5q2rYW1Q7Opz8m709xy6c8ZU1aTSwbHUXsMc1K8hk0tBYemoPUJNTGkFHFQh-gmHRfFQB1tq736a1sdbSsoxVlJvX1cMPcT2v-Zf3oL8PEEYPnmL4dRJePQG7QuFsnKBvfkgj8-J5OJ</recordid><startdate>202002</startdate><enddate>202002</enddate><creator>Veneris, Jennifer Taylor</creator><creator>Matulonis, Ursula A.</creator><creator>Liu, Joyce F.</creator><creator>Konstantinopoulos, Panagiotis A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202002</creationdate><title>Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations</title><author>Veneris, Jennifer Taylor ; Matulonis, Ursula A. ; Liu, Joyce F. ; Konstantinopoulos, Panagiotis A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-460a1aab828b2964a9dcb15fc2191627f639ddad6d8058e694520ec5536ddf473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>BRCA1 Protein - genetics</topic><topic>BRCA2 Protein - genetics</topic><topic>Developmental therapeutics</topic><topic>DNA damage repair</topic><topic>DNA Repair</topic><topic>Female</topic><topic>Genes, BRCA1</topic><topic>Genes, BRCA2</topic><topic>Germ-Line Mutation</topic><topic>Humans</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - immunology</topic><topic>PARP inhibitors</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage</topic><topic>Randomized Controlled Trials as Topic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Veneris, Jennifer Taylor</creatorcontrib><creatorcontrib>Matulonis, Ursula A.</creatorcontrib><creatorcontrib>Liu, Joyce F.</creatorcontrib><creatorcontrib>Konstantinopoulos, Panagiotis A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Veneris, Jennifer Taylor</au><au>Matulonis, Ursula A.</au><au>Liu, Joyce F.</au><au>Konstantinopoulos, Panagiotis A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2020-02</date><risdate>2020</risdate><volume>156</volume><issue>2</issue><spage>488</spage><epage>497</epage><pages>488-497</pages><issn>0090-8258</issn><eissn>1095-6859</eissn><abstract>PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP inhibitor combinations.
•PARP inhibitors (PARPi) have transformed the management of advanced ovarian cancer.•With increased PARPi use, the resistance to PARPi will become a increasing clinical concern.•Combinatorial approaches can overcome de novo and acquired resistance to PARPi by exploiting DDR mechanisms.•PARPi combinations can induce “BRCAness”, inhibit DNA repair, promote replication stress, or enhance immunomodulation.•Selection of the appropriate combination for the clinical context could overcome, or prevent, PARPi resistance.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31630846</pmid><doi>10.1016/j.ygyno.2019.09.021</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Combined Chemotherapy Protocols - administration & dosage BRCA1 Protein - genetics BRCA2 Protein - genetics Developmental therapeutics DNA damage repair DNA Repair Female Genes, BRCA1 Genes, BRCA2 Germ-Line Mutation Humans Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - immunology PARP inhibitors Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage Randomized Controlled Trials as Topic |
| title | Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations |
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