Graduation Date

Fall 12-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Dr. Nicole Shonka, MD

Second Advisor

Dr. Surinder K Batra, PhD

Abstract

Glioblastoma (GBM) is one of the most common and lethal primary malignant brain and central nervous system (CNS) tumors. It accounts for 50.9% of all malignant tumors, with an annual incidence rate of 3.27 per 100,000 population in the United States. Despite the multiple treatment approaches, the median survival is only eight months with a 5-year survival rate of 6.9%, and the tumor almost always recurs with a dismal prognosis. Ionizing radiation and specific genetic syndromes are associated with a high incidence of GBM. Interestingly, patients with a history of asthma, allergy, or atopy have fewer incidences of GBM (RR = 0.59, 95% CI 0.49-0.71). Additionally, histamine, a mediator of allergy, has been studied in various cancers, demonstrating its critical involvement in proliferation, angiogenesis, migration, and invasion. Furthermore, recent literature shows that GBM patients with low HRH1 expression have better survival than those with high HRH1 expression, and electronic medical records indicate that patients taking antihistamines during treatment have better survival than those without antihistamines.

We used a bioinformatics tool, iLINCS, which analyzes the transcriptomic and proteomic datasets and signatures of cellular perturbations to identify novel targets for unique therapeutic approaches. Based on the concordance score and blood-brain barrier permeability (BBB), we selected brompheniramine (Brom), a first-generation histamine 1 receptor (HRH1) antagonist, as a potential candidate to reverse the GBM signature.

We showed that HRH1 is highly expressed in human GBM cell lines and in mouse orthograft tissue sections compared to normal astrocytes and brain parenchyma, respectively, and that expression is significantly higher in GBM than in low-grade glioma. We have shown that histamine can cause a dose-dependent increase in proliferation and decrease the sensitivity of GBM cells to TMZ. Additionally, in combination with temozolomide (TMZ), Brom enhanced TMZ's antitumor efficacy in vitro by inhibiting proliferation, inducing S-phase cell cycle arrest, and promoting apoptosis.

Furthermore, we have demonstrated that the combination treatment of TMZ and Bom significantly reduces tumor burden in vivo and prolongs survival in both the orthograft and patient-derived xenograft models. These findings emphasize the promising potential of targeting HRH1 as an innovative therapeutic strategy to improve outcomes for patients facing these challenging tumors.

Comments

2025 Copyright, the authors

Additional Files
BBA reveiw in cancer policy.pdf (92 kB)
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