Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers
Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administe...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.631135/full |
| _version_ | 1818734036587118592 |
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| author | Timothy Crook Darshana Patil Andrew Gaya Nicholas Plowman Sewanti Limaye Anantbhushan Ranade Amit Bhatt Raymond Page Dadasaheb Akolkar |
| author_facet | Timothy Crook Darshana Patil Andrew Gaya Nicholas Plowman Sewanti Limaye Anantbhushan Ranade Amit Bhatt Raymond Page Dadasaheb Akolkar |
| author_sort | Timothy Crook |
| collection | DOAJ |
| description | Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation (ETA: Encyclopedic Tumor Analysis) yields significant treatment response and survival benefits in advanced or refractory solid organ cancers.Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy naïve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS).Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths.Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers.Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548. |
| first_indexed | 2024-12-17T23:58:59Z |
| format | Article |
| id | doaj.art-a1f3ca322e8a4c56b65ea71ee2da2f76 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-17T23:58:59Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a1f3ca322e8a4c56b65ea71ee2da2f762022-12-21T21:28:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-04-011210.3389/fphar.2021.631135631135Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic CancersTimothy Crook0Darshana Patil1Andrew Gaya2Nicholas Plowman3Sewanti Limaye4Anantbhushan Ranade5Amit Bhatt6Raymond Page7Dadasaheb Akolkar8Broomfield Hospital, Chelmsford, United KingdomDatar Cancer Genetics, Nasik, IndiaHCA Healthcare United Kingdom, London, United KingdomSt Bartholomew’s Hospital, London, United KingdomKokilaben Dhirubhai Ambani Hospital, Mumbai, IndiaAvinash Cancer Clinic, Pune, IndiaAvinash Cancer Clinic, Pune, IndiaWorcester Polytechnic Institute, Worcester, IndiaDatar Cancer Genetics, Nasik, IndiaBackground: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation (ETA: Encyclopedic Tumor Analysis) yields significant treatment response and survival benefits in advanced or refractory solid organ cancers.Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy naïve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS).Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths.Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers.Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548.https://www.frontiersin.org/articles/10.3389/fphar.2021.631135/fullencyclopedic tumor analysisETAmTORPIK3CAPI3KAkt |
| spellingShingle | Timothy Crook Darshana Patil Andrew Gaya Nicholas Plowman Sewanti Limaye Anantbhushan Ranade Amit Bhatt Raymond Page Dadasaheb Akolkar Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers Frontiers in Pharmacology encyclopedic tumor analysis ETA mTOR PIK3CA PI3K Akt |
| title | Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers |
| title_full | Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers |
| title_fullStr | Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers |
| title_full_unstemmed | Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers |
| title_short | Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers |
| title_sort | improved treatment outcomes by using patient specific drug combinations in mammalian target of rapamycin activated advanced metastatic cancers |
| topic | encyclopedic tumor analysis ETA mTOR PIK3CA PI3K Akt |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.631135/full |
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