FGF19 positive Solid Tumors

Aberrant fibroblast growth factor 19 (FGF19) signaling mediated by its receptor, FGF receptor 4 (FGFR4), and coreceptor, klotho β (KLB), is a driver of hepatocellular carcinoma (HCC). Several potent FGFR4-selective inhibitors have been developed but have exhibited limited efficacy in HCC clinical trials. Here, by using HCC cell line models from the Cancer Cell Line Encyclopedia (CCLE) and the Liver Cancer Model Repository (LIMORE), we show that selective FGFR4 inactivation was not sufficient to inhibit cancer cell proliferation and tumor growth in FGF19-positive HCC. Moreover, genetic inactivation of KLB in these HCC cells resulted in a fitness defect more severe than that resulting from inactivation of FGFR4. By a combination of biochemical and genetic approaches, we found that KLB associated with FGFR3 and FGFR4 to mediate the prosurvival functions of FGF19. KLB mutants defective in interacting with FGFR3 or FGFR4 could not support the growth or survival of HCC cells. Genome-wide CRISPR loss-of-function screening revealed that FGFR3 restricted the activity of FGFR4-selective inhibitors in inducing cell death; the pan-FGFR inhibitor erdafitinib displayed superior potency than FGFR4-selective inhibitors in suppressing the growth and survival of FGF19-positive HCC cells. Among FGF19-positive HCC cases from The Cancer Genome Atlas (TCGA), FGFR3 is prevalently coexpressed with FGFR4 and KLB, suggesting that FGFR redundancy may be a common mechanism underlying the de novo resistance to FGFR4 inhibitors. Our study provides a rationale for clinical testing of pan-FGFR inhibitors as a treatment strategy for FGF19-positive HCC.

Photodynamic therapy (PDT) can destroy local tumor cells and induce effective antitumor immune responses, and has been applied in the treatment of patients with superficial solid tumors. Numerous systemic side effects of PDT, such as pain and skin photosensitivity, however, limit this therapeutic option. In addition, the immunosuppressive tumor microenvironment has been found to be another critical barrier for the antitumor immunity induced by PDT. Therefore, effectively enhancing the cytotoxicity to tumor cells of low-dose PDT and inhibiting the tumor immunosuppressive tumor microenvironment may be a feasible strategy to overcome these drawbacks of PDT. Here, a sorafenib and chlorin e6 co-loaded reactive oxygen species (ROS)-responsive nanoparticle (NP-sfb/ce6) is developed to improve antitumor responses by intratumoral release of sorafenib at the time of PDT. Under 660-nm laser irradiation, ROS produced by chlorin e6 (ce6) destruct the nanoparticles, resulting in boosted sorafenib cascade release. The rapidly released sorafenib acts synergistically with the low-dose PDT to inhibit tumor growth by inducing strong T cell-dependent local and systemic antitumor immune responses, reprograming the tumor immune microenvironment, and limiting the interaction between cytotoxic CD8⁺ T cells and immunosuppressive cells. This study provides new avenues for cascade-amplifying antitumor effects of photodynamic therapy.

Neonatal tumors are different from tumors of the older children and knowledge gained from treating older children can not be extrapolated to neonates. Neonates have immature physiology and their haematopoietic and immune systems are not fully developed and the response to therapy is unpredictable. Hence it is imperative to study these tumors as separate entity. The aim of this study is to analyse this rare set of tumors in terms of their incidence, clinical features and management.

All babies admitted in our hospital with tumors from January, 2011 to January 2016 were studied. Tumor-like conditions like haemangioma, lymphangioma and hamartomas were included. The age, sex distribution, type of tumor and management were studied.

A total of 51 cases were registered out of which, 29 cases were haemangiomas and lymphangiomas. Of remaining 20 cases, 5 were benign ovarian cysts, 3 were neuroblastomas, 3 were congenital fibrosarcomas, 3 were sacrococcygeal teratomas. Wilm's tumor, congenital mesoblastic nephroma, haemangioendothelioma of liver and others formed the remaining six cases.

Our study insists that the neonatal tumors are distinct subset of pediatric tumors, requiring careful selection of treatment modalities and most of the solid tumors can be successfully managed if diagnosed and treated early. Neonatal tumors are defined as tumors which are diagnosed before the first month of life. Some of them can be congenital (present at birth). Neonatal tumors are different from tumors in older children in terms of etiopathogenesis, behavior and response to therapy as well as long-term outcomes.