Translational Studies to facilitate Rational Therapeutic Combinations of Letrozole for the Treatment of Glioblastoma

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The prognosis for patients with glioblastoma (GBM), one of the most lethal brain tumors, remains dismal. Our recent discoveries provide robust evidence suggesting that letrozole (LTZ), an aromatase inhibitor used in the treatment of breast cancer, has the potential to be a breakthrough therapeutic for the treatment of GBM. Our data include: 1) LTZ treatment of patient-derived GBM cells markedly reduced cell viability and spheroid growth; 2) LTZ potentiated the activity of temozolomide (TMZ), the primary agent used in chemotherapy of GBM in TMZ- resistant cells; 3) Pharmacokinetics/Pharmacodynamics (PK/PD) studies in immunocompetent rats orthotopically implanted with C6 rat glioma revealed that LTZ readily crosses the blood-brain barrier (BBB), markedly reduces tumor volume and extends survival (10 vs. > 60 days in control vs. LTZ); and 4) immunohistochemical analysis of tissues (N > 90 patients) demonstrated that the aromatase expression is strikingly higher (> 5X) in GBM relative to low-grade gliomas. Moreover, in an ongoing phase 0/1 clinical trial in which recurrent GBM patients received LTZ (2.5 -12.5 mg, N = 14 subjects) prior to surgical resection, analyses of the excised tumor revealed that LTZ readily traverses the BBB in humans. RNAseq analysis showed significant downregulation of oncogenes driving cell proliferation markers and upregulation of tumor suppression markers (reduced DNA damage repair capacity) in a LTZ dose-dependent manner. Our long-term goal is to repurpose LTZ as an anti-GBM drug. Given the phenotypic/genotypic complexity of GBM, combination therapy will be a clinical necessity. To support this goal, our objective here is to conduct comprehensive PK/PD studies of LTZ and combination agents in patient-derived orthotopic xenograft (PDOX) immunodeficient (athymic nude) rats. Typically, such studies are performed utilizing athymic/SCID mice. However, the elimination half-life of LTZ in mice is short (~ 2.5 hours), whereas LTZ PK in rats are closer to that in humans requiring the use of athymic nude rats. Thus, we propose to conduct a quantitative milestone-based study employing primary and recurrent patient-derived GBM. We will rigorously test combination agents for LTZ, strongly suggested collectively by our RNAseq and other data and rationally advance 2-3 combinations for phase II clinical trials. Specific Aims: 1: Rank-order combination partners for LTZ based on synergistic effects against GBM lines in vitro 2: Determine in vivo BBB permeability of combination agents ± LTZ. 3: Establish PDOX athymic nude rat models for in vivo PK/PD studies, 4: Evaluate PK/PD of LTZ ± combination agent employing the PDOX models. The R61 phase milestones include synergistic inhibition of cell viability (Combination Index, CI< 1) and BBB permeability (plasma to brain partitioning) (Aims 1 and 2). Concurrently, an athymic nude rat models will be established/validated in Aim 3. Using these models in the R33 phase (Aim 4), dose-response relationship will be derived to advance 2-3 LTZ combinations to phase II clinical trials. A multidisciplinary team of collaborators will participate in this important next step to repurpose LTZ for GBM treatment, an urgent unmet medical need.