Benedito A. Carneiro

Repurposing metformin for cancer treatment: current clinical studies

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

Emerging therapeutic targets in bladder cancer

Treatment of muscle invasive urothelial bladder carcinoma (BCa) remains a major challenge. Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets. This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa. Small molecule pan-FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations. mTOR inhibitors for patients with TSC1 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K/AKT/mTOR pathway. Encouraging preclinical results with ado-trastuzumab emtansine (T-DM1) exemplifies a new potential treatment for HER2-positive BCa along with innovative bispecific antibodies. Inhibitors of cell cycle regulators (aurora kinase, polo-like kinase 1, and cyclin-dependent kinase 4) are being investigated in combination with chemotherapy. Early results of clinical studies with anti-CTLA4 and anti-PDL1 are propelling immune modulating drugs to the forefront of emerging treatments for BCa. Collectively, these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy.

Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.

Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials

Purpose Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. Methods PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. Results Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. Conclusion Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.

Metastatic Basal Cell Carcinoma: Complete Response to Chemotherapy and Associated Pure Red Cell Aplasia

Basal cell carcinoma (BCC) is usually a benign and indolent cancer cured in greater than 95 percent of cases. Nevertheless, it can be locally destructive or occasionally metastasize to distant organs. We report a case of BCC metastatic to the lungs, occurring 17 years after the primary BCC was noticed, that responded to carboplatin and paclitaxel on 3 occasions. The patient also developed pure red cell aplasia (PRCA). Work-up did not reveal underlying thymoma or infectious, rheumatologic, or lymphoproliferative disorders. Parvovirus serologies were negative, and antibodies against erythropoetin were not detected. There was no history of exposure to drugs associated with PRCA. Bone marrow biopsy on 2 different occasions did not show evidence of myelodysplasia. PRCA may represent an unusual paraneoplastic syndrome associated with BCC as reported with other carcinomas. This is the first report of PRCA associated with metastatic BCC or the drugs carboplatin and paclitaxel, which were used to treat it. The literature on chemotherapy for metastatic BCC is reviewed.

Wnt/beta-catenin pathway: modulating anticancer immune response

Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA

Genomic analysis of tumor tissue is the standard technique for identifying DNA alterations in malignancies. Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a relatively non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance of genomic alterations between cfDNA and tissue biopsies in this retrospective study. Twenty-eight patients with advanced solid tumors with paired next-generation sequencing tissue and cfDNA biopsies were identified. Sixty-five genes were common to both assays. Concordance was defined as the presence or absence of the identical genomic alteration(s) in a single gene on both molecular platforms. Including all aberrations, the average number of alterations per patient for tissue and cfDNA analysis was 4.82 and 2.96, respectively. When eliminating alterations not detectable in the cfDNA assay, mean number of alterations for tissue and cfDNA was 3.21 and 2.96, respectively. Overall, concordance was 91.9–93.9%. However, the concordance rate decreased to 11.8–17.1% when considering only genes with reported genomic alterations in either assay. Over 50% of mutations detected in either technique were not detected using the other biopsy technique, indicating a potential complementary role of each assay. Across 5 genes (TP53, EGFR, KRAS, APC, CDKN2A), sensitivity and specificity were 59.1% and 94.8%, respectively. Potential explanations for the lack of concordance include differences in assay platform, spatial and temporal factors, tumor heterogeneity, interval treatment, subclones, and potential germline DNA contamination. These results highlight the importance of prospective studies to evaluate concordance of genomic findings between distinct platforms that ultimately may inform treatment decisions.

FGFR3-TACC3: A novel gene fusion in cervical cancer.

Cervical cancer epitomizes the success of cancer prevention through the human papillomavirus (HPV) vaccine, but significant challenges remain in the treatment of advanced disease. We report the first three cases of cervical carcinoma harboring an FGFR3–TACC3 fusion, which serves as a novel therapeutic target. The fusion, identified by comprehensive genomic profiling, activates the FGFR pathway that has been implicated in HPV-driven carcinogenesis. One of the patients whose tumor contained the FGFR3–TACC3 fusion was treated with an investigational FGFR tyrosine kinase inhibitor. Concomitant molecular alterations involving the PI3K/AKT/mTOR and RAF/MEK pathways were also identified and suggest other treatment strategies that deserve investigation. This case series highlights the role of comprehensive genomic profiling in the identification of new therapeutic targets and in targeted therapy selection for patients with cervical cancer.

Adenoid cystic carcinoma: current therapy and potential therapeutic advances based on genomic profiling

Adenoid cystic carcinoma (ACC) is a rare cancer with high potential for recurrence and metastasis. Efficacy of current treatment options, particularly for advanced disease, is very limited. Recent whole genome and exome sequencing has dramatically improved our understanding of ACC pathogenesis. A balanced translocation resulting in the MYB-NFIB fusion gene appears to be a fundamental signature of ACC. In addition, sequencing has identified a number of other driver genes mutated in downstream pathways common to other well-studied cancers. Overexpression of oncogenic proteins involved in cell growth, adhesion, cell cycle regulation, and angiogenesis are also present in ACC. Collectively, studies have identified genes and proteins for targeted, mechanism-based, therapies based on tumor phenotypes, as opposed to nonspecific cytotoxic agents. In addition, although few studies in ACC currently exist, immunotherapy may also hold promise. Better genetic understanding will enable treatment with novel targeted agents and initial exploration of immune-based therapies with the goal of improving outcomes for patients with ACC.

Targeted therapies in advanced differentiated thyroid cancer.

Differentiated thyroid cancer is the most common endocrine malignancy, and its incidence has been rising rapidly over the past 10 years. Although most patients with this disease have an excellent prognosis, a subset develops a more aggressive disease phenotype refractory to conventional therapies. Until recently, there was no effective therapy for these patients. With increasing knowledge of the molecular pathogenesis of thyroid cancer, novel targeted therapies are being developed for this group of patients. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. This represents a major innovation in the therapy of patients with advanced thyroid cancer. However, these therapies still have many limitations and further research needs to be pursued with the ultimate goal of providing safe and effective personalized therapy for patients with advanced thyroid cancer.