Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation

Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation

The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 77; no. 11; pp. 2869 - 2880
Main Authors: Frazier, Jason P, Bertout, Jessica A, Kerwin, William S, Moreno-Gonzalez, Alicia, Casalini, Joey R, Grenley, Marc O, Beirne, Emily, Watts, Kori L, Keener, Andy, Thirstrup, Derek J, Tretyak, Ilona, Ditzler, Sally H, Tripp, Chelsea D, Choy, Kevin, Gillings, Sarah, Breit, Megan N, Meleo, Karri A, Rizzo, Vanessa, Herrera, Chamisa L, Perry, James A, Amaravadi, Ravi K, Olson, James M, Klinghoffer, Richard A
Format: Journal Article
Language:English
Published: United States American Association for Cancer Research, Inc 01-06-2017
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Antitumor activity
Autophagy
Cancer
Cell Line, Tumor
Chemotherapy
Complexity
Dogs
Doxorubicin
Drug development
Drug Resistance, Multiple
Humans
Immune system
Immunomodulation
Immunomodulation - immunology
Immunosuppressive agents
Macrophages
Metastases
Microinjection
Neoplasms - drug therapy
Patients
Phagocytosis
Precision medicine
Precision Medicine - methods
Sarcoma
Soft tissue sarcoma
Tumors
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Summary:The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. .
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J.P. Frazier, J.A. Bertout, and W.S. Kerwin contributed equally to this article.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-17-0084