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PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA -mutated human epidermal growth factor receptor 2–negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α =.10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P <.001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non–small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION: Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration–approved. Talazoparib showed activity in patients with BRCA-mutated tumors for which PARP inhibitors are not yet FDA-approved. @ASCO #TAPUR [ABSTRACT FROM AUTHOR]

Purpose: In this study, we describe the geographic distribution of US cancer treatment trials to identify disparities and opportunities for targeted improvements in access to research for people with cancer., Methods: US-based phase I-III cancer treatment trials registered on ClinicalTrials.gov were tabulated for the years they were open to enrollment (2017-2022), overall and by county, and supplemented with data from the US Census Bureau, National Cancer Institute, Centers for Disease Control and Prevention, and US Department of Agriculture. We evaluated geographic differences in trial availability. We assessed 5-year trends in trials per capita and mapped 1-hour drive time areas around sites., Results: A total of 6,710 trials were open to enrollment in 2022 across 1,836 sites. Trials increased by 4%, whereas sites decreased by 3% annually per capita from 2017. Seventy percent of US counties had no reported active trials in 2022 (2,211/3,143), representing 19% of people age ≥55 years. Eighty-six percent of nonmetropolitan counties had no trials versus 44% of metropolitan counties. Trial availability varied by county-level cancer mortality and social vulnerability (an index derived from demographic and socioeconomic data from the US Census). Eighteen percent of counties without trials had oncologist care sites (n = 618). Notably, 26% of people age ≥55 years lived beyond an hour drive of a site with ≥100 trials., Conclusion: Most US counties have limited to no trial offerings, a disparity magnified in counties that are nonmetropolitan, with high social vulnerability, and with high cancer mortality. Effort to facilitate diverse site participation is needed to promote equitable access to trials and to ensure patients participating in trials match the characteristics of patients who will receive interventions once approved. Counties with oncology care sites but no trials provide potential expansion areas.

Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment., (©2023 American Association for Cancer Research.)

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in patients with breast cancer. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis. In addition to programming tumor cell behavior, Hh activity enables tumor cells to craft a metastasis-conducive microenvironment. Hypoxia is a prominent feature of growing tumors that impacts multiple signaling circuits that converge upon malignant progression. We investigated the role of Hh activity in crafting a hypoxic environment of breast cancer. We used radioactive tracer [ 18 F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia. We show that tumors competent for Hh activity are able to establish a hypoxic milieu; pharmacologic inhibition of Hh signaling in a syngeneic mammary tumor model mitigates tumor hypoxia. Furthermore, in hypoxia, Hh activity is robustly activated in tumor cells and institutes increased HIF signaling in a VHL-dependent manner. The findings establish a novel perspective on Hh activity in crafting a hypoxic tumor landscape and molecularly navigating the tumor cells to adapt to hypoxic conditions. IMPLICATIONS: Importantly, we present a translational strategy of utilizing longitudinal hypoxia imaging to measure the efficacy of vismodegib in a preclinical model of triple-negative breast cancer., (©2021 American Association for Cancer Research.)

Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in patients with cancer. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages. Treatment with the pharmacologic Hh inhibitor vismodegib induced a significant shift in the profile of tumor-infiltrating macrophages. Mass spectrometry-based metabolomic analysis showed Hh inhibition induced significant alterations in metabolic processes, including metabolic sensing, mitochondrial adaptations, and lipid metabolism. In particular, inhibition of Hh in M2 macrophages reduced flux through the UDP-GlcNAc biosynthesis pathway. Consequently, O-GlcNAc-modification of STAT6 decreased, mitigating the immune-suppressive program of M2 macrophages, and the metabolically demanding M2 macrophages shifted their metabolism and bioenergetics from fatty acid oxidation to glycolysis. M2 macrophages enriched from vismodegib-treated mammary tumors showed characteristically decreased O-GlcNAcylation and altered mitochondrial dynamics. These Hh-inhibited macrophages are reminiscent of inflammatory (M1) macrophages, phenotypically characterized by fragmented mitochondria. This is the first report highlighting the relevance of Hh signaling in controlling a complex metabolic network in immune cells. These data describe a novel immunometabolic function of Hh signaling that can be clinically exploited. SIGNIFICANCE: These findings illustrate that Hh activity regulates a metabolic and bioenergetic regulatory program in tumor-associated macrophages that promotes their immune-suppressive polarization., (©2021 American Association for Cancer Research.)