Brain metastases (BM) have a 90% mortality rate within 4-12 months of diagnosis because they are mainly treated palliatively. The Singh Lab uses patient-derived BM samples in clinically relevant xenograft models of BM that recapitulate BM progression as seen in human patients. The objectives of my thesis were twofold: to understand whether targeting pre-metastatic cells could intercept BM formation, and whether macro-metastatic BM tumors could respond to immunotherapy as an alternative to palliative care. To intercept BM formation, I mined a Connectivity Map analysis on pre-metastatic BM gene expression signatures and identified a key regulator of the pre-metastatic process. Pharmacological and genetic perturbation of this target attenuates BMIC proliferation in vitro and slows down the formation of BM in vivo, highlighting a targetable metabolic vulnerability in BM. This work has inspired a preclinical drug development program focused on creating inhibitors with enhanced brain permeation for clinical translation. To identify whether macro-metastatic tumors respond to immunotherapy, we used a chimeric antigen receptor (CAR) T-cell to target the glycoprotein CD133, whose expression correlates with disease progression, recurrence, chemo- and radio-resistance and overall poor prognosis. We saw significant impediment in tumor progression and significant survival advantage in tumor-bearing mice after a single dose. Together, I propose that prophylaxis should be the focus of BM research moving forward and that immunotherapies should be considered where BM diagnosis precedes the chance for interception. The development of a drug that can eradicate pre-metastatic cells has the potential to prevent BM in at-risk cancer patients, while the development of a CD133-targetting immunotherapy can dramatically improve the prognosis of patients who would otherwise be limited to palliative care. / Thesis / Doctor of Philosophy (PhD) / Brain metastases have a 90% mortality rate within one year of diagnosis because they are largely untreatable. The objectives of this research were twofold: to understand whether we can prevent BM, and to understand whether developed metastatic brain tumors respond to immunotherapy. We discovered that inhibition of the enzyme inosine monophosphate dehydrogenase (IMPDH) prevents the growth of brain metastases cells. This inspired an ongoing drug development program aiming to develop IMPDH inhibitors as drugs that prevent metastatic brain cancer. To identify whether metastatic brain tumors respond to immunotherapy, we used a CAR-T cell immunotherapy to target the glycoprotein CD133 and found that tumor growth was delayed or completely blocked after a single dose. Based on these results, we propose that therapeutics that prevent the formation of brain metastases are a promising strategy to combat this deadly disease. Furthermore, we have shown that immunotherapies are a viable strategy for the treatment of brain metastases.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/28560 |
| Date | January 2023 |
| Creators | Kieliszek, Agata |
| Contributors | Singh, Sheila, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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