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ImportanceDespite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial.ObjectiveTo determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone.Design, Setting, ParticipantsThe External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022.InterventionsPatients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression.Main Outcomes and MeasuresThe primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing.ResultsThe study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm.Conclusions and RelevanceIn this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals.Trial RegistrationClinicalTrials.gov Identifier: NCT03599765

Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here, we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In our study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved antitumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.

Background: The aim of the present investigation was to evaluate the effects of the administration of a juice containing essential nutrients (marine omega-3 fatty acids: EPA and DHA, a polyphenolrich juice, vitamin D3, essential amino acids and dietary fibre) (CAX) and a juice also enriched with curcumin (CUR), alone or in combination with a chemotherapeutic agent ( sorafenib ) in a mouse cancer cachexia model. Methods: Administration of CAX and CUR in the form of jellified pellets to mice bearing the Lewis lung carcinoma. Results: Administration of CAX and CUR in the form of jellified pellets to mice bearing the Lewis lung carcinoma resulted in a 12 and 18% reduction in tumour weight, respectively, but no additive effect in combination with sorafenib was seen. No effects on metastases measurements were observed. In spite of the reduction of the primary tumour, the chemotherapy treatment alone did not result in any changes in body weight. Conversely, in combination with sorafenib, both juices had an important effect on body weight loss. CUR also had an effect without chemotherapy. Concerning muscle weight, tibialis muscle mass was increased as a result of CAX and CUR treatment. Sorafenib-treated mice had a tendency towards larger tibialis muscles, this tendency being clearly significant when CAX was administered in combination with chemotherapy. In sorafenib-treated mice, juice treatment --either CAX or CUR-- resulted in a tendency to an increase in grip force. Conclusions: It is concluded that administration of omega-3/protein and omega-3/protein/curcumin-enriched fruit juices may have beneficial effects on muscle wasting and could be part of a multi-modal therapy for cancer cachexia.

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES-bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.

312 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and MET. These receptors regulate several immune suppressive cell types in the tumor microenvironment, including M2-polarized macrophages, MDSCs, and T regulatory cells, which are implicated in resistance to checkpoint inhibitors. ccRCC is characterized by upregulation of VEGF and overexpression of MET and AXL. Sitra may combine effectively with immune checkpoint inhibition to augment antitumor activity in ccRCC. About 39% of patients with accRCC who receive surgery with curative intent relapse representing an unmet need in this setting. Together these data support the evaluation of neoadjuvant sitra with nivo in accRCC. Methods: This phase II study (NCT03680521) evaluated sitra and nivo in pts with locally- advanced ccRCC who were candidates for curative nephrectomy. Single-agent sitra (120 mg) was administered daily (QD) for 2 weeks, with nivo (240 mg intravenously Q2W) added to sitra for 4-6 weeks. A plan for potential dose de-escalation was implemented using a modified toxicity probability interval method with a maximum toxicity of 20% at the tolerated dose. Pts underwent pathology/tissue evaluation at 3 timepoints: biopsy prior to treatment, biopsy prior to the addition of nivo, and nephrectomy specimen evaluation at time of nephrectomy. The primary endpoint was objective response (RECIST 1.1); secondary endpoints included safety, PK, and correlative immune effects (selected protein and gene expression and immune cell populations). Results: A total of 20 pts were evaluated for safety (95% had T3 or higher stage tumors, 65% with baseline hypertension). Dose-limiting toxicities (DLTs) led to a dose de-escalation, resulting in 7 pts treated at 120 mg QD sitra and 13 pts treated at 80 mg QD. DLTs included grade 3 (Gr3) hypertension (n=6); deep vein thrombosis and pulmonary embolism (Gr3) were observed in 1 additional pt. Median duration of sitra treatment was 6.3 weeks at the 80 mg dose and 7.1 weeks at the 120 mg dose. With a median follow-up of 9.4 months after initiation of systemic therapy, no pts have relapsed. In 17 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 11.8%, including 2 PRs (33.3% ORR in pts who received 120 mg sitra). No pts experienced progressive disease while on therapy. Median DFS was not reached. There was 1 delayed surgery due to nivo-related thyroiditis that resolved. Reported TRAEs: Gr1/Gr2 in 55% of pts (dysphonia 50%, fatigue 45%, diarrhea 40%, hypertension 30%, increased ALT 30%), Gr3 in 45% of pts (hypertension 30%). There were no Gr4/Gr5 TRAEs. Correlative blood and tissue analyses will be presented. Conclusions: The combination of sitra and nivo is clinically active with a manageable safety profile as a neoadjuvant therapy for accRCC. Clinical trial information: NCT03680521 .

Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.

Chemotherapy efficacy is reliant upon access to tumor cells. One method of increasing chemotherapy response is to enhance delivery of chemotherapy to the tumor by vascular normalization. Tumor vasculature is largely dysfunctional, leading to poor delivery of chemotherapy. Vascular normalization, the remodeling of tumor vessels to increase functionality, has been shown to improve drug delivery and response in patients with glioblastoma, ovarian and colorectal cancers. Current normalization strategies using anti-angiogenic agents have a narrow dose and time therapeutic window. Therefore, it is imperative to identify other methods of inducing tumor vessel normalization to enhance the delivery and efficacy of chemotherapy. Vascular development, and endothelial cell (EC) signaling, is controlled by shear stress. Shear stress is the mechanical force exerted on ECs by blood flow through the vessel lumen. The role of shear stress in tumor vessel development is poorly understood. Tumors have heterogeneous, low levels of vascular shear stress. Heterogeneous, low shear stress causes hyper-permeable vessels that inefficiently deliver blood throughout the tumor. Aerobic exercise is a well-studied method for increasing vascular shear stress. We demonstrated in mouse models of Ewing sarcoma and melanoma that increasing shear stress via moderate exercise caused improved tumor vascular function including reduced hyper-permeability. This correlated with significantly increased chemotherapy delivery and efficacy; doxorubicin was significantly more effective against both tumor models when combined with exercise. The molecular mechanisms of tumor vascular remodeling in response to exercise, particularly the decrease in vessel permeability leading to better drug delivery, are unclear. Vascular permeability is regulated in part via Sphingosine-1-Phosphate Receptors 1 and 2 (S1PR1, S1PR2) on ECs, which have contrasting effects on angiogenesis. S1PR1 signaling increases adherens junctions, decreasing vascular permeability. In contrast, S1PR2 signaling increases vessel permeability. We found that S1PR1 was increased while S1PR2 was decreased on tumor endothelium of exercised mice. We have now identified the novel regulator of tumor endothelial permeability, ERK5, as a key mediator of improved tumor vascular function in response to exercise. Pharmacologic activation of S1PR1 by SEW2871 or activation of ERK5 signaling by p90RSK decreased tumor vascular hyper-permeability and increased doxorubicin efficacy, mimicking the exercise effect. Ongoing work using inducible S1PR1 or ERK5 knockout mice will determine whether this pathway is essential for exercise-induced tumor vascular remodeling and improved chemotherapeutic efficacy. Citation Format: Hannah Savage, Enrica Marmonti, Claudia Bedoya, Miriam Garcia, Keri Schadler. Exercise as a novel method of tumor vascular remodeling [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 5012.

Background: Type 2 Diabetes Mellitus affects more than 350 million people worldwide. This metabolic disorder is characterized by insulin resistance, β-cell dysfunction and elevated hepatic glucose output. Patients with diabetes are hospitalized frequently (3-fold greater) and with longer admissions (30% longer) than the non-diabetic subjects. The aim of the study was to investigate the impact of bed rest on the metabolic changes in type II diabetes mellitus, with particular interest in skeletal muscle mass and function and metabolism. Methods: 13wk old male Zucker diabetic fatty (ZDF) rats were randomly divided into two groups: control (ZDF-Con) and cage-immobilized animals (ZDF-Cage) for 28 consecutive days in a space-restricted cage. Results: The Area Under the Curve (AUC) values for plasma glucose concentration in ZDF-Cage rats were significantly increased (approximately 4-fold as compared with ZDF-Con rats). GLUT4 gene expression in red soleus muscle of ZDF-Cage animals was reduced 2.5-fold in comparison with ZDF–Con rats. Although no apparent changes were observed either in fasting plasma glucose or insulin levels, a trend towards an increase in the HOMA-IR index and decreased levels of plasma adiponectin (-30%) were observed in ZDF-Cage animals. Moreover, ZDF-Cage rats did not lose muscle mass and force but performed a reduced total physical activity level (-22%). Conclusions: The present study results suggests that 28 days of immobilization --in a space-restriction model-- significantly impaired glucose tolerance with concomitant reduced plasmatic adiponectin levels and GLUT-4 expression in soleus muscle of type 2 diabetic rats.

Background The effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre-clinical rodent models, where only the tumour-induced alterations are taken into account, excluding the co-presence of anti-tumour molecules that could worsen the scenario and/or interfere with the treatment. Methods The aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour-bearing rats (Yoshida AH-130, a highly cachectic tumour) undergoing chemotherapy (sorafenib). Results Treatment of cachectic tumour-bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi-factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour-bearing animals. The effects of the multi-factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems. Conclusions The combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre-clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

Summary Background & aims Tumour growth is associated with weight loss resulting from both adipose and muscle wasting. Methods Administration of l -carnitine (1 g/kg body weight) to rats bearing the AH-130 Yoshida ascites hepatoma, a highly cachectic rat tumour. Results The treatment results in a significant improvement of food intake and in muscle weight (gastrocnemius, EDL and soleus). These beneficial effects are directly related to improved physical performance (total physical activity, mean movement velocity and total travelled distance). Administration of l -carnitine decreases proteasome activity and the expression of genes related with this activity, such as ubiquitin, C8 proteasome subunit and MuRF-1. Interestingly, l -carnitine treatment also decreases caspase-3 mRNA content therefore suggesting a modulation of apoptosis. Moreover, addition of 50 μM of l -carnitine to isolated EDL muscles results in a significant decrease in the proteolytic rate suggesting a direct effect. Conclusions It can be concluded that l -carnitine supplementation may be a good approach for a multi-targeted therapy for the treatment of cancer-related cachexia.

Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.

Summary Background & aims Cachexia is a multi-organic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. The aim of the present investigation was to study the effects of megestrol acetate (MA) on the rate of leucine incorporation into muscle tissue and on the uptake of AIB (a non-metabolizable analogue of alanine) in both skeletal muscle and liver tissue. Methods The effects of MA (100 mg/kg) were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Tissue amino acid uptake was assessed by means of the alanine analogue α-amino-3H-isobutyrate (AIB). 14C-leucine oxidation and tissue protein incorporation were also determined. Results Administration of MA to tumour-bearing rats resulted in an important reversal of the muscle wasting process, as reflected by individual muscle weights. Treatment with the progestogen resulted in an increased AIB uptake together with an increased leucine incorporation in skeletal muscle. MA treatment significantly decreased AIB uptake by the liver. Conclusions MA treatment results in both a significant increased uptake of neutral amino acids (AIB) by skeletal muscle and a significant incorporation of the branched-chain amino acid leucine into muscle protein, indicating a clear anabolic action of the drug on muscle tissue.

Cachexia is a common systemic manifestation. Additionally, myostatin is known to be a negative regulator of skeletal muscle development. The present study aimed to investigate whether formoterol down-regulates the myostatin system in skeletal muscle of tumour-bearing rats. Real-time PCR and Western blotting were used for the analysis. Results showed that rats bearing the Yoshida AH-130 ascites hepatoma, a cachexia-inducing tumour, exhibited marked muscle wasting that affected the mass of the muscles studied. The cachectic animals exhibited a significant increase in the mRNA levels of the myostatin receptor (ActIIB) in gastrocnemius muscles. Notably, the expression of the various forms of follistatin, a protein with the opposite effects to those of myostatin, was significantly reduced as a result of the implantation of the tumour. When the animals were treated with formoterol, a β-agonist with anti-cachectic potential, increases in skeletal muscle weights were observed. The β-agonist significantly increased levels of various follistatin isoforms and significantly decreased the expression levels of the myostatin receptor. In addition, formoterol treatment resulted in a significant decrease of the myostatin protein content of the gastrocnemius muscle. In conclusion, the results presented indicate that certain anabolic actions of formoterol on the skeletal muscle of cachectic animals may be mediated via the myostatin system.

Bed rest has been an established treatment in the past prescribed for critically illness or convalescing patients, in order to preserve their body metabolic resource, to prevent serious complications and to support their rapid path to recovery. However, it has been reported that prolonged bed rest can have detrimental consequences that may delay or prevent the recovery from clinical illness. In order to study disuse-induced changes in muscle and bone, as observed during prolonged bed rest in humans, an innovative new model of muscle disuse for rodents is presented. Basically, the animals are confined to a reduced space designed to restrict their locomotion movements and allow them to drink and eat easily, without generating physical stress. The animals were immobilized for either 7, 14, or 28 days. The immobilization procedure induced a significant decrease of food intake, both at 14 and 28 days of immobilization. The reduced food intake was not a consequence of a stress condition induced by the model since plasma corticosterone levels -an indicator of a stress response- were not altered following the immobilization period. The animals showed a significant decrease in soleus muscle mass, grip force and cross-sectional area (a measure of fiber size), together with a decrease in bone mineral density. The present model may potentially serve to investigate the effects of bed-rest in pathological states characterized by a catabolic condition, such as diabetes or cancer.