Selected Articles from This Issue

Keytruda® pembrolizumab is an approved treatment for multiple cancer indications. Given the clinical impact of pembrolizumab and the continuing research to improve PD-1-related immunotherapies, better understanding of the molecule's preclinical characterization is important. Pembrolizumab binds to human PD-1 with picomolar affinity and antagonizes the binding of both PD-L1 and PD-L2 to PD-1, a key feature of its clinical mechanism of action. Pembrolizumab binds via the HCDR3 loop to both the C'D and FG loop. of PD-1. The affinity of pembrolizumab is hypothesized to be due to this binding epitope, which is distinct from other anti-PD-1 agents.

Metastatic bone lesions are present in 20-35% of patients with renal cell carcinoma (RCC) and severely impact patient mobility and survival. Previous research by Pan and colleagues identified that a transforming growth factor-beta-inducing protein ig-h3 (Beta ig-h3) (BIGH3) suppresses osteoblast differentiation and prevents the healing of these osteolytic regions. Here, they demonstrate that stimulating osteoblast differentiation (cabozantinib) prevents osteolysis in preclinical models of RCC bone metastasis. Using a 3D co-culture system, they demonstrate the effects of cabozantinib and BMP4 (to promote bone formation) on overcoming BIGH3-inhibited osteoblast differentiation. In vivo studies confirmed the potential for cabozantinib in restricting bone lesions. These results support the development of clinical trials of cabozantinib with osteoanabolic agents for RCC.

The 5-year overall survival rate for locally advanced head and neck cancer remains approximately 50% and has not changed over the past few decades. Cisplatin and radiation remain the treatment mainstay. To enhance this mainstay, Zeng and colleagues added the CHK1/2 inhibitor prexasertib. This addition increased persistent DNA damage, owing in part to the downregulation of NOTCH signaling. The addition of prexasertib to cisplatin and radiation abrogated the G2/M checkpoint, induced S-phase accumulation, and increased apoptosis. Based on their results, a clinical study has completed accrual (NCT02555644).

Patients with pancreatic cancer often require dose reductions of chemotherapy regimens due to their cumulative toxicities, usually at the expense of efficacy. Desmoplasia of these tumors is a significant barrier to effective treatment, and reducing it by stromal reprogramming of these tumors would allow for lower systemic doses of chemotherapy to be administered while still delivering a critical concentration to the tumor to maintain efficacy. Anbil and colleagues employ photodynamic priming (PDP), a sub-therapeutic dose of photodynamic therapy that modulates the tumor microenvironment, to achieve this effect. They demonstrate that PDP combined with a vitamin D analogue abrogated metabolic changes induced by cancer-associated fibroblasts. In an orthotopic mouse model of pancreatic cancer, the combined therapy allowed a 75% reduction in nal-IRI (from 20 mg/kg to 5 mg/kg) while maintaining tumor control.