We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [¹⁸F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes. We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [¹⁸F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [¹⁸F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry. In a preclinical mouse model, we illustrated that [¹⁸F]PARPi crossed the blood–brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [¹⁸F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood–brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen. Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [¹⁸F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

Purpose: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). Patients and Methods: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. Results: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8–9.2] with 1-year PFS at 23.7% (95% CI, 12.4%–45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3–14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. Conclusions: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.

Introduction Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. Methods A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 C_min), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. Results Of the 24 enrolled patients, median age was 62.1 (38.7–76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6–2.5) and OS was 7.7 months (95% CI 4.9–12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R² = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. Conclusions PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

Severe radiation-related lymphopenia is common and associated with decreased survival in patients with several solid tumors. As the mechanisms underlying systemic lymphopenia are poorly understood, we developed an animal model to study the effects of brain radiation on lymphocytes and cytokines. C57 BL/6 and BALB/c mice received focal brain irradiation (4 Gy x 10 fractions or 2 Gy x 30 fractions). Weekly total lymphocyte counts (TLC), lymphocyte subsets and cytokines in blood and lymph nodes were measured. Non-irradiated lymph nodes were collected and examined before, during, and after radiation. We found that systemic TLC decreased rapidly irrespective of mouse strain or radiation schedule. 4 Gy x 10 resulted in a 42% and 75% & 70% and 49% TLC reduction in C57 BL/6 and BALB/c mice respectively. 2 Gy x 30 caused a 70% / 49% decrease in TLC in C57 BL/6 and BALB/c. Similar trends were seen for total T cells, CD4⁺, regulatory T and CD8⁺ cells. Changes in lymph node architecture and cellular composition correlated with the development of systemic lymphopenia. Three weeks after radiation, TLC returned to 60–80% of baseline, preceded by increased IL-7 levels in the lymph nodes. Focal brain radiation in mice results in significant systemic lymphodepletion.