Targeted therapies for renal cell carcinoma.

The management of patients with metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. Nephrectomy remains an important intervention for localized RCC but systemic therapy is the mainstay of treatment for patients who relapse after surgery or who have metastatic RCC. Before 2005, medical therapies for RCC were limited to cytokine therapies, which are very toxic and benefit only a small percentage of patients. In 2017, therapeutic agents now include kinase and immune checkpoint inhibitors. Contemporary research with these agents is now focusing on combinatorial and perioperative therapy. The field is now faced with the evolving challenge of how to select the best therapy for each patient during their natural history of disease, which has created a strong interest in modern sequencing and molecular approaches to identify biomarkers to personalize treatments. New therapeutic agents and approaches are associated with different toxicities and financial burdens, which require consideration of value by measuring clinical benefit, toxicity, and the cost of each drug with an organized framework. In this Review, we discuss the mechanisms underlying RCC and how improved molecular understanding helped the development of therapies, as well as biomarkers of response to treatment. We also discuss the value of these agents and their impact on personalization of therapy and drug development for RCC.

Targeting angiogenesis in renal cell carcinoma.

INTRODUCTION: Understanding the molecular pathogenesis of renal cell carcinomas (RCC) has identified targets for therapeutic intervention. The recognition of the importance of hypoxia-inducible factor-1α (HIF-1α) signaling in the pathogenesis of clear-cell RCC has led to widespread study of angiogenesis inhibitors. While the major component of the angiogenic process in RCC is VEGF, targeting of the mTOR pathway is important because activation of the upstream PI3K/Akt/mTOR signaling pathways is one method by which constitutive HIF-1α activation or upregulation occurs. AREAS COVERED: Current FDA-approved anti-angiogenic agents as first- and second-line treatment for RCC, as well as agents in development will be reviewed. EXPERT OPINION: Novel agents targeting non-VEGFR signals in kidney cancer will be met with new successes and new challenges in therapeutic development. While several of these agents will likely show activity, they may accentuate toxicity. Careful triage of these agents paired with biomarker studies will facilitate development of these agents and identification of those patients most likely to benefit from these emerging therapies.

Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic oncology database.

BACKGROUND: In recent years, there has been tremendous growth and interest in translational research, particularly in cancer biology. This area of study clearly establishes the connection between laboratory experimentation and practical human application. Though it is common for laboratory and clinical data regarding patient specimens to be maintained separately, the storage of such heterogeneous data in one database offers many benefits as it may facilitate more rapid accession of data and provide researchers access to greater numbers of tissue samples. DESCRIPTION: The Thoracic Oncology Program Database Project was developed to serve as a repository for well-annotated cancer specimen, clinical, genomic, and proteomic data obtained from tumor tissue studies. The TOPDP is not merely a library-it is a dynamic tool that may be used for data mining and exploratory analysis. Using the example of non-small cell lung cancer cases within the database, this study will demonstrate how clinical data may be combined with proteomic analyses of patient tissue samples in determining the functional relevance of protein over and under expression in this disease. Clinical data for 1323 patients with non-small cell lung cancer has been captured to date. Proteomic studies have been performed on tissue samples from 105 of these patients. These tissues have been analyzed for the expression of 33 different protein biomarkers using tissue microarrays. The expression of 15 potential biomarkers was found to be significantly higher in tumor versus matched normal tissue. Proteins belonging to the receptor tyrosine kinase family were particularly likely to be over expressed in tumor tissues. There was no difference in protein expression across various histologies or stages of non-small cell lung cancer. Though not differentially expressed between tumor and non-tumor tissues, the over expression of the glucocorticoid receptor (GR) was associated improved overall survival. However, this finding is preliminary and warrants further investigation. CONCLUSION: Though the database project is still under development, the application of such a database has the potential to enhance our understanding of cancer biology and will help researchers to identify targets to modify the course of thoracic malignancies.

Kinase inhibitors in prostate cancer.

Prostate cancer is a significant public health problem around the world. Once a patient has disease that is no longer addressable by local means, the cancer is considered incurable. Therapeutic goals at this point include not only extension of survival but also alteration of the natural history which may otherwise lead to significant pain and morbidity from the disease process- all related to metastases. While effective systemic therapies do currently exist, their roles are considered limited for many patients. Given the overwhelming incidence and annual mortality figures related to prostate cancer, there continues to be an urgent need for therapeutic advances. Protein kinases have emerged as "druggable" therapeutic targets as they control a multitude of basic cellular activities, including growth, survival, proliferation, differentiation and apoptosis. Several of these kinases have oncogenic properties as in the setting of malignancy they may be overactive and/or dysregulated leading to the excessive proliferation and motility typical of cancer cells. Small molecule inhibitors have shown efficacy in several tumor models and are actively being studied in prostate cancer. This review summarizes historical and contemporary studies evaluating kinase inhibitors in the treatment of prostate cancer.

Pazopanib: therapeutic developments.

Pazopanib (Votrient, GW786034) is a potent pan-VEGF inhibitor in advanced clinical development. Like other orally available VEGFR inhibitors, pazopanib is clinically efficacious and well tolerated. The recently reported Phase III clinical trial in metastatic renal cell carcinoma showed activity similar to approved agents with variations in toxicity which has led to its recent FDA approval. Given the growing number of agents in this category, differences not only in single-agent activity but also toxicity and combinatorial potency will probably distinguish pazopanib from other similar agents.