Discovery Medicine

Abstract: The impact of KRAS mutations on the efficacy of therapies that target the epidermal growth factor receptor (EGFR) is a major, ongoing area of oncology research, aimed at identifying the best possible treatments for individual colon cancer patients. Because patients with KRAS mutant colorectal tumors rarely respond to anti-EGFR monoclonal antibodies, testing is required to confirm the patient's tumor is KRAS wild-type before utilizing these therapies. Despite being studied for more than 30 years, new information continues to develop regarding KRAS and its role in colon carcinogenesis. This information must be integrated into the development of effective colon cancer treatment strategies. This review will summarize recent evidence that most, if not all, colon tumors encompass at least a subpopulation of KRAS mutant cells, meaning tumors characterized as KRAS wild-type are in most cases tumors with relatively low KRAS mutant tumor cell content. Recent studies support the hypothesis that relapse in advanced colorectal patients treated with EGFR-targeted monoclonal antibody therapy involves the outgrowth of previously undetected KRAS mutant tumor cell populations. Studies investigating the effects of oxidative stress on Ras signaling suggest that the frequent presence of minor KRAS mutant tumor cell populations may be a consequence of hypoxic conditions within tumors, which produce a negative selection against KRAS mutant cells in polyclonal tumors. Thus, the literature and current practices for characterizing tumor KRAS mutation don't accurately reflect the nature of colon tumor KRAS mutation, even though an accurate understanding is critical for identifying the best strategies for intervention. ... Read more

Abstract: The outcome of patients with myeloma has improved significantly in the past decade with the incorporation of the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor, bortezomib. Considering nearly all patients relapse, myeloma remains an active area of investigation. There are several promising classes of agents including next generation immunomodulatory agents, proteasome inhibitors, antibody and antitumor immunotherapy approaches that are being evaluated. This article provides an overview on the therapeutic strategies in the treatment of multiple myeloma. ... Read more

Abstract: Asthma is a common chronic disease characterized by intermittent chest symptoms, variable airways obstruction, and bronchial hyperresponsiveness. Research performed over the past one to two decades has sought to better understand the heterogeneous clinical nature of asthma. Whereas older attempts at phenotyping asthma emphasized the duality of allergic vs. non-allergic asthma, more recent non-biased analyses have attempted to cluster patients by a multitude of possible features, including age of onset, atopy, severity of airways obstruction, and requirement for medication. Examples of these phenotypes include early-onset mild allergic asthma, later-onset asthma associated with obesity, and severe non-atopic asthma with frequent exacerbations. The elucidation of asthma phenotypes has been further refined by including information regarding pathophysiologic mechanisms present in different groups. These groups, called endotypes, include examples such as aspirin-exacerbated respiratory disease and allergic bronchopulmonary mycosis. A growing understanding of these mechanistically distinct groups, along with the identification of relevant cellular or molecular biomarkers, is already showing promise as a way of predicting clinical response to various asthma therapies. As the number of targeted treatments for asthma continues to grow, physicians will have the opportunity to practice an individualized approach to diagnosis and treatment, which will hopefully improve asthma outcomes and quality of life for these patients. ... Read more

Abstract: The use of targeted oral anticancer medications (OAMs) is becoming increasingly prevalent in cancer care. Approximately 25-30% of the oncology drug pipeline involves oral agents and there are now over 50 OAMs approved by the Food and Drug Administration. This change represents a major shift in management of patients with cancer from directly observed, intermittent intravenous therapy to self-administered, oral chronic therapy. The increased prevalence of OAMs raises the issue of adherence in oncology, including understanding the challenges of adherence to OAMs. This review focuses on studies of adherence for patients taking molecularly targeted OAMs for breast cancer, chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). We then discuss barriers to adherence and studies performed to date testing interventions for improving adherence. Finally, we discuss future areas of investigation needed to define and improve adherence to OAMs in targeted therapy for cancer. ... Read more

Abstract: Glioblastoma (GBM) is the most deadly form of human cancer. Most patients diagnosed with this WHO grade IV malignant glioma survive about 12 months. Despite international efforts, treatment of GBM remains one of the most challenging tasks in clinical oncology. While new molecular pathways active in the biology and invasiveness of glioma are being constantly discovered, translation of basic science achievements into clinical practice is rather slow. Advances in surgical approaches, radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with GBM and improved quality of life. Yet much more significant strides need to be made before we can witness positive outcomes, similar to those seen in certain other cancers that can now be treated successfully. This review will discuss standard of care approach to GBM therapy in a newly diagnosed and recurrent setting. It will summarize the recent developments in management of this disease as well as future directions, keeping a practicing clinician in mind. ... Read more

Abstract: Mitochondria and their associated genome are emerging as sophisticated indicators of prostate cancer (PCa) biology. Alterations in the mitochondrial genome (mtgenome) have been implicated in cell proliferation, metastatic behavior, androgen independence, as a signal for apoptosis, and as a predictor of biochemical recurrence. Somatic mutation patterns in complete mtgenomes are associated with prostate specific antigen levels (PSA) in PCa patients and a large-scale mtgenome deletion (3.4kb) is consistent with a prostate "cancerization" field effect. This review will focus on the biological characteristics of mitochondria and their direct clinical application to PCa. Mitochondrial science is currently influencing clinical PCa diagnostics and the rapid progress in this area indicates future, break-through contributions in the general field of oncology. ... Read more

Abstract: With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-α in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-α antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies. ... Read more

Abstract: Heterogeneity within the cell population is a feature of many tumors. This lack of cellular homogeneity may originate from a number of sources, including differential nutrient status due to the de novo microcirculations of tumors, to infiltration of normal cells into the tumor, and to the hierarchical natures of the cell populations from which cancers arise. Tumors are thought to arise from one or more tumor initiating cells (TIC) within the population and to found hierarchies of progenitors and more differentiated cancer cells. TIC are often derived from tissue stem cells and these cancer stem cells are characterized by resistance to most cytotoxic treatments and by a high metastatic rate. Many of the properties of tumor populations, including the ability to express mutated oncogenes and to evolve new features such as treatment resistance and invasive and metastatic potential appear to depend on the molecular chaperone Hsp90. We discuss the potential of targeting the heterogeneous cell population with Hsp90 inhibitory drugs and its potential ability to inactivate TIC and to block the evolution of new phenotypes in cancer. ... Read more

Abstract: Mantle cell lymphoma (MCL), which accounts for about 6% of non-Hodgkin lymphoma (NHL), is characterized by the chromosomal translocation t(11;14) (q13;q32), resulting in de-regulated expression of cyclin D1. Managing MCL is challenging, because it is incurable with conventional chemotherapy as with indolent NHL, but has a more aggressive natural history. Therapeutic advances have been made in the past decade with the incorporation of targeted therapies into the frontline setting, use of aggressive combination regimens followed by consolidation with high dose therapy and autologous stem cell rescue for a younger population, use of less aggressive combinations in the elderly, and translation of pre-clinical findings to the clinical trial realm with novel agents that hold significant promise in the treatment of this disease. The authors review current standard approaches in the treatment of MCL, and novel findings in the pathogenesis of this disease that may guide the way for further development of modern therapeutic approaches. ... Read more

Abstract: A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance. ... Read more