Huang, Haozhe
(2023)
Novel Immunochemotherapy for Cancer Treatment.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cancer is a major health issue known for the emergence of resistance to various treatments. Exploring the new mechanism concerning the origin and traits of cancer can help develop innovative approaches that bypass resistance pathways, or combination therapies tackling cancer from multiple angles.
Inflammation is widely acknowledged as a critical catalyst for cancer. Cyclooxygenase (COX), a well-known inflammatory enzyme, leads to tumor progression and therapeutic failure. Therefore, understanding the response of tumor-derived COX to COX inhibitors could be pivotal for cancer therapy. We developed a new micellar carrier (PASA) based on 5-aminosalicylic acid (5-ASA, a COX inhibitor) to enhance codelivery of 5-ASA and doxorubicin (DOX). Inhibition of COX by PASA or PASA/DOX activated the tumor immune microenvironment, leading to improved therapeutic outcomes in CT26 tumors with high COX expression. Our data suggest that PASA may represent a novel and effective delivery system.
To explore the efficacy of PASA in other tumors with high levels of COX, we further employed the PASA polymer to load cisplatin for treatment of lung cancer, which overexpresses COX-2. We identified the roles of AKT1 and COX-2 in cisplatin resistance and cisplatin-induced enrichment of cancer stem cells. Moreover, we established a novel combination therapy based on codelivery of cisplatin, MK2206 (an AKT1 inhibitor) and 5-ASA (a COX-2 inhibitor) by PASA polymer, eliminating both dormant cancer stem cells and proliferative cancer cells. The triple combination (PASA/CDDP/MK2206) significantly reduced tumor burden by reversing the immunosuppressive tumor environments.
We further improved properties of PASA polymers by synthesizing improved PASA (PASA-in) polymers via introducing different spacers between the backbone and 5-ASA. After examining the size of PASA-in, the top two PASA-in polymers were selected to treat BRAFV600E colorectal cancer (CRC), characterized by an elevated level of COX-2. Patients with tumors bearing the BRAFV600E mutation only have limited effective treatments and faces a dismal prognosis. These polymers showed the smallest size and were subsequently used to co-load Dabrafenib (a BRAF inhibitor), Trametinib (a MEK inhibitor), and Alpelisib (a PI3K inhibitor). In vivo therapeutic study revealed that this triple combination controlled the growth of human BRAFV600E CRC cell (WiDr) derived tumor with the highest survival rate.
Collectively, PASA-in could potentially be a promising and effective therapeutic for COX sufficient tumors.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
4 August 2023 |
| Date Type: |
Publication |
| Defense Date: |
19 July 2023 |
| Approval Date: |
4 August 2023 |
| Submission Date: |
3 August 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
182 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Polymer, immunochemotherapy |
| Date Deposited: |
04 Aug 2023 18:18 |
| Last Modified: |
04 Aug 2023 18:18 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45235 |
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