Peptide Binder to Glypican-3 as a Theranostic Agent for Hepatocellular Carcinoma.

Glypican-3 (GPC3) is a membrane-associated glycoprotein that is significantly upregulated in hepatocellular carcinomas (HCC) with minimal to no expression in normal tissues. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy to treat HCC, a leading cause of cancer-related deaths worldwide. Methods: DOTA-RYZ-GPC3 (RAYZ-8009) comprises a novel macrocyclic peptide binder to GPC3, a linker, and a chelator that can be complexed with different radioisotopes. The binding affinity was determined by surface plasma resonance and radioligand binding assays. Target-mediated cellular internalization was radiometrically measured at multiple time points. In vivo biodistribution, monotherapy, and combination treatments with 177Lu or 225Ac were performed on HCC xenografts. Results: RAYZ-8009 showed high binding affinity to GPC3 protein of human, mouse, canine, and cynomolgus monkey origins and no binding to other glypican family members. Potent cellular binding was confirmed in GPC3-positive HepG2 cells and was not affected by isotope switching. RAYZ-8009 achieved efficient internalization on binding to HepG2 cells. Biodistribution study of 177Lu-RAYZ-8009 showed sustained tumor uptake and fast renal clearance, with minimal or no uptake in other normal tissues. Tumor-specific uptake was also demonstrated in orthotopic HCC tumors, with no uptake in surrounding liver tissue. Therapeutically, significant and durable tumor regression and survival benefit were achieved with 177Lu- and 225Ac-labeled RAYZ-8009, as single agents and in combination with lenvatinib, in GPC3-positive HCC xenografts. Conclusion: Preclinical in vitro and in vivo data demonstrate the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3-positive HCC.

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.

Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.

Immediate Effects of Mirror Therapy in Patients With Shoulder Pain and Decreased Range of Motion.

OBJECTIVE: To determine the effects of a brief single component of the graded motor imagery (GMI) sequence (mirror therapy) on active range of motion (AROM), pain, fear avoidance, and pain catastrophization in patients with shoulder pain. DESIGN: Single-blind case series. SETTING: Three outpatient physical therapy clinics. PARTICIPANTS: Patients with shoulder pain and limited AROM (N=69). INTERVENTION: Patients moved their unaffected shoulder through comfortable AROM in front of a mirror so that it appeared that they were moving their affected shoulder. MAIN OUTCOME MEASURES: We measured pain, pain catastrophization, fear avoidance, and AROM in 69 consecutive patients with shoulder pain and limited AROM before and immediately after mirror therapy. RESULTS: There were significant differences in self-reported pain (P=.014), pain catastrophization (P<.001), and the Tampa Scale of Kinesiophobia (P=.012) immediately after mirror therapy; however, the means did not meet or exceed the minimal detectable change (MDC) for each outcome measure. There was a significant increase (mean, 14.5°) in affected shoulder flexion AROM immediately postmirror therapy (P<.001), which exceeded the MDC of 8°. CONCLUSIONS: A brief mirror therapy intervention can result in statistically significant improvements in pain, pain catastrophization, fear avoidance, and shoulder flexion AROM in patients presenting with shoulder pain with limited AROM. The immediate changes may allow a quicker transition to multimodal treatment, including manual therapy and exercise in these patients. Further studies, including randomized controlled trials, are needed to investigate these findings and determine longer-term effects.