Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer
Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/16/2/257 |
| _version_ | 1797344465581506560 |
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| author | Sareh Seyedi Ruthanne Teo Luke Foster Daniel Saha Lida Mina Donald Northfelt Karen S. Anderson Darryl Shibata Robert Gatenby Luis H. Cisneros Brigid Troan Alexander R. A. Anderson Carlo C. Maley |
| author_facet | Sareh Seyedi Ruthanne Teo Luke Foster Daniel Saha Lida Mina Donald Northfelt Karen S. Anderson Darryl Shibata Robert Gatenby Luis H. Cisneros Brigid Troan Alexander R. A. Anderson Carlo C. Maley |
| author_sort | Sareh Seyedi |
| collection | DOAJ |
| description | Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043–1.1, <i>p</i> = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024–0.55, <i>p</i> = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013–0.42, <i>p</i> = 0.003). Overall, the survival time increased with reduced dose for both single drugs (<i>p</i> < 0.01) and combined drugs (<i>p</i> < 0.001), resulting in tumors with fewer proliferation cells (<i>p</i> = 0.0026) and more apoptotic cells (<i>p</i> = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined. |
| first_indexed | 2024-03-08T11:03:02Z |
| format | Article |
| id | doaj.art-242676cec9204fd087314c1111327e26 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T11:03:02Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-242676cec9204fd087314c1111327e262024-01-26T15:34:08ZengMDPI AGCancers2072-66942024-01-0116225710.3390/cancers16020257Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast CancerSareh Seyedi0Ruthanne Teo1Luke Foster2Daniel Saha3Lida Mina4Donald Northfelt5Karen S. Anderson6Darryl Shibata7Robert Gatenby8Luis H. Cisneros9Brigid Troan10Alexander R. A. Anderson11Carlo C. Maley12Arizona Cancer Evolution Center, Arizona State University, Tempe, AZ 85287, USASchool of Life Sciences, Arizona State University, Tempe, AZ 85287, USAArizona Cancer Evolution Center, Arizona State University, Tempe, AZ 85287, USAArizona Cancer Evolution Center, Arizona State University, Tempe, AZ 85287, USADivision of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, AZ 85054, USADivision of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, AZ 85054, USASchool of Life Sciences, Arizona State University, Tempe, AZ 85287, USADepartment of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USADepartment of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL 33629, USAArizona Cancer Evolution Center, Arizona State University, Tempe, AZ 85287, USADepartment of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 27606, USADepartment of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL 33629, USAArizona Cancer Evolution Center, Arizona State University, Tempe, AZ 85287, USAAdaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043–1.1, <i>p</i> = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024–0.55, <i>p</i> = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013–0.42, <i>p</i> = 0.003). Overall, the survival time increased with reduced dose for both single drugs (<i>p</i> < 0.01) and combined drugs (<i>p</i> < 0.001), resulting in tumors with fewer proliferation cells (<i>p</i> = 0.0026) and more apoptotic cells (<i>p</i> = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined.https://www.mdpi.com/2072-6694/16/2/257adaptive therapyendocrine-resistant MCF7 breast cancerhigh-dose therapydrug-resistant and drug-sensitive subclones |
| spellingShingle | Sareh Seyedi Ruthanne Teo Luke Foster Daniel Saha Lida Mina Donald Northfelt Karen S. Anderson Darryl Shibata Robert Gatenby Luis H. Cisneros Brigid Troan Alexander R. A. Anderson Carlo C. Maley Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer Cancers adaptive therapy endocrine-resistant MCF7 breast cancer high-dose therapy drug-resistant and drug-sensitive subclones |
| title | Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer |
| title_full | Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer |
| title_fullStr | Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer |
| title_full_unstemmed | Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer |
| title_short | Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer |
| title_sort | testing adaptive therapy protocols using gemcitabine and capecitabine in a preclinical model of endocrine resistant breast cancer |
| topic | adaptive therapy endocrine-resistant MCF7 breast cancer high-dose therapy drug-resistant and drug-sensitive subclones |
| url | https://www.mdpi.com/2072-6694/16/2/257 |
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