Purpose 223Ra-Dichloride (223Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent. Methods Ten patients received either 50, 100, or 200 kBq of 223Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed. Results Pharmacokinetic studies showed rapid clearance of 223Ra from the vasculature, with a median of 14 % (range 9–34 %), 2 % (range 1.6–3.9 %), and 0.5 % (range 0.4–1.0 %) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52 % of administered 223Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4 % of administered 223Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients. Conclusion 223Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.

We examined sugar-induced obesity in mouse strains polymorphic for Tas1r3, a gene that codes for the T1R3 sugar taste receptor. The T1R3 receptor in the FVB and B6 strains has a higher affinity for sugars than that in the AKR and 129P3 strains. In Experiment 1, mice had 40 days of access to lab chow plus water, sucrose (10 or 34%), or fructose (10 or 34%) solutions. The strains consumed more of the sucrose than isocaloric fructose solutions. The pattern of strain differences in caloric intake from the 10% sugar solutions was FVB > 129P3 = B6 > AKR; and that from the 34% sugar solutions was FVB > 129P3 > B6 ≥ AKR. Despite consuming more sugar calories, the FVB mice resisted obesity altogether. The AKR and 129P3 mice became obese exclusively on the 34% sucrose diet, while the B6 mice did so on the 34% sucrose and 34% fructose diets. In Experiment 2, we compared total caloric intake from diets containing chow versus chow plus 34% sucrose. All strains consumed 15-29% more calories from the sucrose-supplemented diet. In Experiment 3, we compared the oral acceptability of the sucrose and fructose solutions, using lick tests. All strains licked more avidly for the 10% sucrose solutions. The results indicate that in mice (a) Tas1r3 genotype does not predict sugar-induced hyperphagia or obesity; (b) sucrose solutions stimulate higher daily intakes than isocaloric fructose solutions; and (c) susceptibility to sugar-induced obesity varies with strain, sugar concentration and sugar type.

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Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas. It is characterized by significant disease heterogeneity with variable sites of origin and diverse genomic profiles. As a result, the treatment of advanced leiomyosarcoma is challenging. First-line therapy for metastatic and/or unresectable leiomyosarcoma includes anthracycline or gemcitabine based regimens, which provide a median progression-free survival time of about 5 months and overall survival time between 14-16 months. Effective later-line therapies are limited. Molecular profiling has enhanced our knowledge of the pathophysiology driving leiomyosarcoma, providing potential targets for treatment. In this review, we explore recent advances in our understanding of leiomyosarcoma tumor biology and implications for novel therapeutics. We describe the development of clinical trials based on such findings and discuss available published results. To date, the most promising approaches for advanced leiomyosarcoma include targeting DNA damage repair pathways and aberrant metabolism associated with oncogenesis, as well as novel chemotherapy combinations. This review highlights the recent progress made in the treatment of advanced leiomyosarcoma. Ongoing progress is contingent upon further development of clinical trials based on molecular findings, with careful consideration for clinical trial design, strong academic collaborations, and prospective correlative analyses.

Oligometastatic renal cell carcinoma (OM-RCC) refers to patients who have limited (typically up to 5) metastatic lesions. Although management principles may overlap, OM-RCC is distinguishable from oligoprogressive RCC, which describes progression of disease to a limited number of sites while receiving systemic therapy. Cytoreductive nephrectomy and metastasectomy are common surgical considerations in OM-RCC, and indications are discussed in this review. It is evident that stereotactic ablative radiotherapy is effective in RCC and is being applied increasingly in the oligometastatic setting. Finally, we will review advances in systemic therapy and the role of active surveillance before the initiation of systemic therapy.

Background: Prostate-specific membrane antigen is a cell-surface glycoprotein commonly expressed on prostatic adenocarcinomas (PC). PSMA expression is related to AR signaling, generally with increased PSMA expression with dysregulation of the AR pathway. Targeted radionuclide therapies (TRT) involving radionuclides (177Lu, 225Ac, 90Y) conjugated to PSMA-specific antibodies (e.g. J591) or small molecule ligands (e.g. PSMA-617) are being developed and utilized in clinical trials. Genetic profiling of PC may predict responsiveness to PSMA-based therapies. Because of the relationship of AR and PSMA expression, we sought to assess the association between AR genomic aberrations and outcome following PSMA-TRT. Methods: Eligible subjects with progressive metastatic castration-resistant PC were enrolled in prospective PSMA-TRT clinical trials. Those who underwent targeted or whole-exome sequencing of their tumors were analyzed. Pre-treatment baseline clinical data were collected; outcome measures included PSA decline and overall survival (OS) post-therapy. Chi-square test was used to assess the association of AR alterations and PSA decline with multivariable logistic regression to control for known factors associated with response. The Kaplan-Meier method was used to assess OS with multivariable cox proportional hazards regression analysis to evaluate the independent effect of AR alterations on OS after controlling for prognostic variables. Results: 66 men with median age 69.6 years were enrolled. 38 (57%) received 177Lu-PSMA-617, 16 (24%) 177Lu-J591, 7 (11%) 225Ac-J591, and 5 (8%) both 177Lu-PSMA-617 and 177Lu-J591. The majority (59%) were poor-risk CALGB (Halabi) prognostic group. 31 patients (47%) had AR amplifications or resistance mutations. Patients with AR alterations were less likely to experience ≥30% PSA decline (32.3% vs. 62.9%, p=0.025) compared to wild-type, though this association was less significant after controlling for radionuclide dose and PSMA imaging intensity. AR alterations were associated with shortened OS (12.43 vs. 21.07 months, p=0.043). After controlling for radionuclide dose, Halabi group, PSMA imaging intensity, and receipt of subsequent FDA-approved life-prolonging therapies, AR alterations still were associated with shortened OS (HR 2.07 [1.02-4.2], p=0.04). Conclusion: AR resistance mutations and amplifications appear to result in poorer outcome following PSMA-TRT both in terms of PSA decline and overall survival. Genetic sequencing may inform responses to PSMA-based therapies, and prospective genomic panel testing is ongoing. Supported by: Weill Cornell Medicine, Prostate Cancer Foundation, Department of Defense, NIH Citation Format: Michael Sun, Muhammad Niaz, Charlene Thomas, Ariel Schaap, Kristine Lacuna, Panagiotis Vlachostergios, Paul Christos, Ana M. Molina, David M. Nanus, Cora N. Sternberg, Joseph Osborne, Neil H. Bander, Scott T. Tagawa. Androgen receptor (AR) genomic alterations and clinical outcome with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6511.

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