Marijo Bilusic

Objectives: To determine the relationship between gynaecomastia and testosterone levels in patients with biochemically recurrent prostate cancer treated with androgen receptor pathway inhibitor (ARPI) monotherapy. Patients and Methods: This analysis evaluates changes in serum testosterone and the incidence of gynaecomastia. Patients with biochemically recurrent prostate cancer were given 3 months of enzalutamide intermittently with no androgen deprivation. Serum testosterone was within the normal range. Testosterone and adverse events were monitored prospectively. Results: A total of 38 patients were enrolled with a median age of 64.6 years, median (range) serum prostate‐specific antigen level of 4.38 (2.01–19.43) ng/mL, and median (range) serum testosterone level of 316 (167–723) ng/dL. Testosterone had a median peak of 832.5 ng/dL (median increase of 63%). Gynaecomastia symptoms were reported in 16 (42%) patients. There was no correlation with either peak testosterone level or duration of elevated testosterone and gynaecomastia. Patients with gynaecomastia with Course 1 of therapy did not fully predict the incidence of gynaecomastia for Course 2. Conclusions: In this study, there is no direct correlation between ARPI monotherapy‐associated testosterone elevation and the incidence of gynaecomastia. The interactions of ARPI monotherapy, gynaecomastia, and testosterone elevation are more nuanced than previously thought and require further study to optimise ARPI monotherapy in clinical practice.

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Randomized clinical trials have highlighted the importance of weight control and exercise in improving cancer outcomes, yet the molecular mediators of these benefits remain poorly understood. Recent studies in Type 2 diabetic patients reported that the insulin-sensitizing drug, metformin, exerts its anorexigenic and anti-obesogenic effects through elevation of N-lactoyl-phenylalanine (Lac-Phe), a metabolite also reported to underlie the metabolic benefits of exercise in healthy individuals. Because metformin can be repurposed for oncology, we investigated whether the metformin/Lac-Phe link extends to cancer by profiling serum Lac-Phe levels in non-diabetic prostate cancer patients from BIMET-1, a prospective metformin trial, as well as those receiving metformin for metabolic dysfunction. Irrespective of disease stage, anticancer outcomes, or hormone therapy status, metformin treatment significantly and consistently increased serum Lac-Phe in these cancer patients to concentrations that approximated levels reported after strenuous exercise. Moreover, patients on the metformin arm of BIMET-1 exhibited improved weight management following anti-androgen therapy relative to those in the control group. By generalizing the metformin/Lac-Phe axis, our study provides a new molecular context for the metabolic benefits of repurposing metformin in cancer patients.

PURPOSE: Biochemical recurrence (BCR) of prostate cancer (PCa) after definitive surgery and/or radiation (including salvage strategies) is a burgeoning area of clinical research inspired by ultrasensitive next-generation imaging. Most phase III trials in PCa have focused on metastatic disease, defined by conventional imaging. Despite the emergence of new imaging, clinical trial principles from metastatic studies will not optimize future BCR trials. METHODS: A Working Group convened at the National Cancer Institute on November 13, 2024 (NCI BCR WG). Key areas of discussion included nomenclature, baseline criteria for data capture, imaging considerations, delineation of high-risk populations to be targeted for trial development, requirements of metastasis-directed therapy (MDT) or hormonal therapy, quality-of-life considerations, and potential study end points. RESULTS: The NCI BCR WG defined the novel term “prostate-specific membrane antigen (PSMA)+BCR” to identify the emerging concept of recurrent PCa identifiable only on PSMA positron emission tomography (PET), overlapping with BCR and distinct from metastatic hormone-sensitive PCa as traditionally defined by conventional imaging. The WG suggested defining high-risk BCR with a prostate-specific antigen doubling time of ≤6 months, regardless of PET findings. The WG provided recommendations for baseline data capture and imaging requirements. Neither systemic therapy nor MDT were considered mandatory for control arms. The WG also discussed novel end points and quality-of-life metrics in this disease space. CONCLUSION: These discussions should inform future clinical BCR trials in this distinct disease space relative to metastatic disease defined by conventional imaging. The NCI BCR WG strongly advocates that future trials explore deintensification of treatment to minimize toxicity in this relatively indolent disease state.

Cancer vaccines represent a promising approach within immunotherapies. These vaccines are tailored to target tumor-specific antigens, thereby offering a precision approach to cancer treatment. The key principles in developing therapeutic cancer vaccines include identifying appropriate vaccine targets and selecting effective vaccine delivery platforms. These delivery platforms are diverse and have evolved to enhance the immune response. This review explores live cancer vaccines and the biological entities involved. Live cancer vaccines leverage the use of various biological entities to stimulate an immune response. These biological entities including bacterial, yeast-based and viral vectors, have unique properties that can be harnessed to target and destroy cancer cells while eliciting a robust immune response. Clinical trials of cancer vaccines are investigating standalone and combination treatment strategies in the prophylactic, adjuvant, and palliative settings. This review offers insights into the current oncologic vaccine landscape and potential future development.

Neoadjuvant immunotherapy has rapidly evolved as a novel approach in oncology, reshaping the standard treatment for several malignancies, including melanoma, lung, bladder, colorectal, and breast cancer. While it has an acceptable safety profile, challenges persist due to the complexity of the tumor microenvironment (TME), immune evasion, T-cell exhaustion, and identification of biomarkers. Addressing these issues is critical for optimizing treatment regimens, minimizing immune-related adverse events, and ensuring successful clinical integration. This review explores current research on neoadjuvant immunotherapy, emphasizing its impact on standard of care treatment, efficacy, safety, and clinical challenges. A literature search was conducted using PubMed and ClinicalTrials.gov for studies published in the last 5 years. Ongoing research aims to enhance the efficacy of neoadjuvant immunotherapy, identify resistance mechanisms, and broaden indications. Current clinical trials focus on biomarker-driven patient selection, refining immune response modulation through combination strategies, and developing evidence-based protocols for implementation into routine oncology practice. Neoadjuvant immunotherapeutic options have rapidly changed the oncological treatment landscape in only a few years, and this treatment paradigm has quickly become a new standard of care in multiple solid tumors. With continued clinical investigation, neoadjuvant immunotherapy has the dramatic potential to further advance cancer care.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. In this study, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared with the castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer populations, the obligate sGC heterodimer was repressed via methylation of its β subunit. Genetically abrogating sGC complex formation in castration-sensitive prostate cancer cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and cotreatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized the tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell–intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.Significance: Soluble guanylyl cyclase signaling inhibits castration-resistant prostate cancer emergence and can be stimulated with FDA-approved riociguat to resensitize resistant tumors to androgen deprivation, providing a strategy to prevent and treat castration resistance.

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PD-L1 t-haNK cells induce lysis of chordoma cell lines through a PD-L1-mediated mechanism. Two chordoma cell lines (UM-Chor1, JHC7) were used as targets for PD-L1 t-haNK cells in 111In-release killing assays. A, Chordoma cells were analyzed by flow cytometry for PD-L1 expression after 24-hour co-incubation with IFNγ on the same day as killing assays. Cell surface expression of PD-L1 quantified by flow cytometry is reported in % positive cells and MFI. Bold values denote an increase of > 30% relative to untreated control cells. B, Chordoma cells were co-incubated with IFNγ or left untreated as controls for 24 hours before being used as targets for PD-L1 t-haNK cells. All E:T ratios are 20:1. Statistical analyses were done by one-way ANOVA with Tukey's multiple comparisons test. *P d 0.05, **P d 0.01, ***P d 0.001, ****P d 0.0001. Results shown are the means ± SEM of technical triplicate measurements and are representative of three independent experiments.

Targeting of chordoma CSCs through N-601 (anti-PD-L1)-mediated ADCC by N-803 (IL15 superagonist)-activated NK cells. CellTrace Violet-stained UM-Chor1 cells were used as targets for healthy donor NK cells in a flow cytometry-based killing assay. A, CSC and non-CSC subpopulations were identified using the gating strategy described. B, UM-Chor1 cells were co-incubated with N-601 or isotype control antibody and NK cells were treated with N-803 where indicated. CSC and non-CSC cell death through N-601-mediated ADCC by untreated or N-803-treated NK cells were evaluated via flow cytometry using a live/dead fixable cell stain exclusion method. (C and D) Flow cytometry was used to quantify expression of HLA-A,B,C, MICA/B, B7-H6, and PD-L1 expression on CSC and non-CSC UM-Chor1 cells. Cell surface expression of each marker is reported in % positive cells and MFI. Bold values denote an increase of > 20% when comparing CSC vs. non-CSC. All E:T ratios are 5:1. Statistical analyses were done by one-way ANOVA with Tukey's multiple comparisons test. *P d 0.05, **P d 0.01, ***P d 0.001, ****P d 0.0001. Results shown are the means ± SEM of technical quadruplicate measurements and are representative of two independent experiments.