Author ORCID Identifier

0000-0001-8418-9311

Defense Date

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Sandro da Rocha

Abstract

Metastases are the leading cause of cancer-related deaths, and the lungs are one of the primary sites of metastases from several malignancies. Existing therapies fail to entirely eradicate tumors that disseminate and reside in lungs; therefore, patient prognosis significantly worsens. Conventional therapies utilized to treat lung tumors such as chemotherapy are administered systemically and typically exhibit poor lung biodistribution profiles, leading to many undesirable off target effects and suboptimal drug concentration in the tumor, which may promote resistance, further compromising the quality of life of secondary lung cancer patients. Immune cells that infiltrate the tumor microenvironment (TME) play a central role in cancer development, prognosis, and response to therapy, with tumor associated macrophages (TAMs) being one of the most abundant immunosuppressive cells in the TME of many malignancies. Several therapeutic strategies that target TAMs have been proposed. However, such therapeutics are given systemically and present similar challenges as standard of care chemotherapy and other treatments. In this work, we investigate the potential of an alternative strategy to treat lung metastases, in which we target TAMs by local lung administration of colony stimulating factor 1 receptor inhibitors (CSF-1Ris). We report the effects of locally administered CSF-1Ris in i) shifting the balance of TAMs away from the tumorigenic (M2-like) phenotype, ii) modulating the T cell profile and thus repurposing the immune response, and iii) as monotherapy or in combination with chemotherapy, in reducing lung tumor burden.

Rights

© Sulaiman Alhudaithi

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-7-2021

Available for download on Thursday, August 06, 2026

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