Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer
| Autor: | Parastou Foroutan, S. Minton, Robert J. Gillies, Tuhin Das, Pedro M. Enriquez-Navas, Epifanio Ruiz, Sabrina Hassan, Ariosto S. Silva, Robert A. Gatenby, Yoonseok Kam, Gary V. Martinez |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug Paclitaxel medicine.drug_class media_common.quotation_subject Population Breast Neoplasms Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer Cell Line Tumor medicine Animals Humans education Survival analysis Cell Proliferation media_common education.field_of_study medicine.diagnostic_test Cell growth business.industry Magnetic resonance imaging General Medicine medicine.disease Magnetic Resonance Imaging Survival Analysis Disease Models Animal Treatment Outcome 030104 developmental biology chemistry Estrogen 030220 oncology & carcinogenesis Immunology Cancer research Female business |
| Zdroj: | Science Translational Medicine. 8 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aad7842 |
| Popis: | Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors-an evolutionary phenomenon termed "competitive release." We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor-positive (ER(+)) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer. |
| Databáze: | OpenAIRE |
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