There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known. Here, we identify monocarboxylate transporter 1 (MCT-1; encoded by SLC16A1) as a direct target gene supporting Wnt-driven Warburg metabolism. We identify and validate Wnt response elements (WREs) in the proximal SLC16A1 promoter and show that they mediate sensitivity to Wnt inhibition via dominant-negative LEF-1 (dnLEF-1) expression and the small molecule Wnt inhibitor XAV939. We also show that WREs function in an independent and additive manner with c-Myc, the only other known oncogenic regulator of SLC16A1 transcription. MCT-1 can export lactate, the byproduct of Warburg metabolism, and it is the essential transporter of pyruvate as well as a glycolysis-targeting cancer drug, 3-bromopyruvate (3-BP). Using sulforhodamine B (SRB) assays to follow cell proliferation, we tested a panel of colon cancer cell lines for sensitivity to 3-BP. We observe that all cell lines are highly sensitive and that reduction of Wnt signaling by XAV939 treatment does not synergize with 3-BP, but instead is protective and promotes rapid recovery. We conclude that MCT-1 is part of a core Wnt signaling gene program for glycolysis in colon cancer and that modulation of this program could play an important role in shaping sensitivity to drugs that target cancer metabolism.

Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials.

Bladder cancer accounts for nearly 200,000 deaths worldwide yearly. Urothelial carcinoma (UC) accounts for nearly 90% of cases of bladder cancer. Cisplatin-based chemotherapy has remained the mainstay of treatment in the first-line setting for locally advanced or metastatic UC. More recently, the treatment paradigm in the second-line setting was drastically altered with the approval of several immune checkpoint inhibitors (ICIs). Given that only a small subset of patients respond to ICI, further studies have been undertaken to understand potential resistance mechanisms to ICI. One potential resistance mechanism that has been identified in the setting of metastatic UC is the TGF-β signaling pathway. Several pre-clinical and ongoing clinical trials in multiple advanced tumor types have evaluated several therapies that target the TGF-β pathway. In addition, there are ongoing and planned clinical trials combining TGF-β inhibition with ICI, which may provide a promising therapeutic approach for patients with advanced and metastatic UC.

To describe the efficacy of infigratinib, a potent, selective fibroblast growth factor receptor (FGFR) 1–3 tyrosine kinase inhibitor, across lines of therapy (LOT) in patients with metastatic urothelial cancer (mUC). Eligible patients had mUC and prior platinum-based chemotherapy, unless contraindicated, and activating FGFR3 mutation/fusion. Patients received infigratinib 125 mg orally daily (3 weeks on/1 week off) in a single-arm, open-label study. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), best overall response (BOR) that included unconfirmed responses, and overall survival (OS) were also assessed. Subgroup analysis of efficacy and safety outcomes by LOT was performed. Sixty-seven patients were enrolled; 13 (19.4%) received infigratinib as early-line therapy for mUC due to ineligibility to receive platinum-based chemotherapy. Overall, ORR was 25.4% (95% CI 15.5–37.5) and DCR was 64.2% (95% CI 51.5–75.5). ORR was 30.8% (95% CI 9.1–61.4) with early-line infigratinib and 24.1% (95% CI 13.5–37.6) for ≥2 LOT. DCR was 46.2% (95% CI 19.2–74.9) for early-line and 68.5% (95% CI 54.4–80.5) for ≥2 LOT. PFS and OS appeared similar in both groups. Thirteen of 59 patients with a bladder primary tumor received early-line treatment with an ORR of 30.5% (95% CI 9.1–61.4), and 46 received ≥2 LOT with an ORR of 20.3% (95% CI 9.4–33.9); BOR was 38.5% (95% CI: 13.9–68.4%) and 42.6% (95% CI: 29.2–56.8%) in the early-line and salvage settings, respectively. Eight patients with upper tract urothelial carcinoma received salvage therapy (ORR, 50.0%; DCR, 100.0%). No significant differences in toxicities between LOT were observed. Infigratinib has notable activity in patients with mUC regardless of LOT. The findings support the evaluation of infigratinib across different settings in mUC.

In the last couple of decades, breast conservation therapy, which utilizes a combination of surgery, radiotherapy, and endocrine or chemotherapy, has become the standard of care for treating early-stage breast cancer. This practice has been greatly beneficial in the improvement of the patient’s quality of life but has also led to the increased use of radiotherapy and associated soft-tissue sarcomas, with angiosarcoma being the most common malignancy. Radiation-associated angiosarcoma (RAS) of the breast is a rare phenomenon, which has been reported to occur in approximately 0.9 out of 1,000 cases, with a reported onset as late as 23 years following radiotherapy. Here we report 2 cases of RAS that occurred within 6 and 13 years following radiotherapy of their primary breast lesion. We discuss the diagnostic and therapeutic challenges regarding this disease and review the current literature. This case report serves as cautionary lessons on the importance of considering RAS of the breast in the differential diagnosis during evaluation for recurrent breast neoplasms. Ongoing clinical trials using combinations of vascular endothelial growth factor inhibitors and chemotherapy may provide future avenues of treatment for this difficult-to-treat disease.