Background Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. Methods We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. Results RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. Conclusion HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6–1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, “-omic” approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.

Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers.Due to better tolerability, Gemcitabine+Cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer (BC). Nevertheless, predicting treatment failure and overcoming resistance remain as unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in BC and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. Experimental design: V1 expression was measured in muscle-invasive BC (MIBC) specimens by RT-qPCR and immunohistochemistry. HYAL-4 wildtype (Wt) and V1 were stably expressed or silenced in normal urothelial and three BC cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. Results: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to Gemcitabine+Cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to Gemcitabine but not to Cisplatin. V1 expression neither affected Gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased Gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor Tetrahydrouridine resensitized V1-expressing cells to Gemcitabine. While Gemcitabine (25-50-mg/kg) inhibited BC xenograft growth, V1-expressing tumors were resistant. Low-dose combination of Gemcitabine and Tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. Conclusion:V1/Chase drives Gemcitabine resistance and potentially predicts Gemcitabine+Cisplatin failure. CDA inhibition re-sensitizes V1-expressing tumors to Gemcitabine.Since several chemotherapy regimens include Gemcitabine, our study could have broad significance.Research.

<p>Hasanali et al Supplementary Materials</p>