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State of the Art and Future Perspectives for the Use of Insulin-like Growth Factor Receptor 1 (IGF-1R) Targeted Treatment Strategies in Solid Tumors


Cancer Immunotherapy: Present Status, Future Perspective, and a New Paradigm of Peptide Immunotherapeutics

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

The Nuclear Epidermal Growth Factor Receptor Signaling Network and Its Role in Cancer

Abstract: The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer, and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). Although targeting membrane-bound EGFR has shown benefit, a new and emerging role for EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics. ... Read more

Does Large Scale DNA Sequencing of Patient and Tumor DNA Yet Provide Clinically Actionable Information?

Abstract: There have been several publications recently that reported DNA sequence alterations in human tumors. There are gene deletions, amplifications, point mutations, translocations, and other genome changes in these samples compared to normal controls. There is also considerable variation in the number of such changes seen in different cancers. Some of the changes particularly those that are mutations in genes driving cellular proliferation will be useful clinically and could be used to monitor disease. At the present time, however, there are more cost effective ways than whole genome sequencing to derive "clinically actionable information" from the molecular analysis of patients and their tumors when they come into the clinic. The number of clinical options available for patients stratified by molecular diagnostics may actually be limited more by the specific treatments available rather than by the ability to stratify the patients in the first place. ... Read more

Cell Lineage Specification in Tumor Progression and Metastasis

Abstract: Cancer has long been compared to the aberrant development of human tissues. It was in the mid-19th century writings of Rudolf Virchow and Joseph Recamier that malignant tissue was first proposed to originate from embryonal cells. More contemporary perspectives on malignant progression are founded on the tenant that tumors emerge from somatic tissues. Yet examples linking the biological properties of cancer to developmental processes, both aberrant and normal, abound. In this review, we will discuss how the developmental lineage of tumor cells can influence the course of cancer metastasis. As new molecular mechanisms that control cell fate in various tissues are being rapidly uncovered, understanding how these well orchestrated programs can be subverted in human diseases should provide intriguing avenues for fundamental biological discoveries and new therapeutic opportunities in cancer. ... Read more

Tracking the Seed and Tending the Soil: Evolving Concepts in Metastatic Breast Cancer

Abstract: Metastasis, the process whereby cancer cells spread from their primary site of origin and grow in adjacent or distant sites, is the primary cause of death in cancer patients. The last 30 years has witnessed significant progress in decreasing cancer mortality rates -- largely as a result of improved screening and prevention, practical applications of cancer genomics, and less toxic, more targeted therapies. Despite these improvements, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. Historically, metastasis has been described as a unidirectional process, whereby cancer cells leave a primary tumor and seed metastasis in regional lymph nodes or distant sites. This anatomically based hypothesis has dictated much of our medical, and in particular, surgical approach to treating cancers. Alternatively, recent research indicates that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. The multidirectional pathway of cancer cells, termed "self-seeding," has been corroborated in several experimental and clinical models. This review will evaluate the "self-seeding" hypothesis with attention both to the "seed" (cancer cells) as well as the "soil" (premetastatic niche). Increasingly, the role of the microenvironment surrounding metastases appears essential to the survival of metastatic colonies. The self-seeding model depends not only on the inherent mobility of cancer cells, but also on the supporting non-cancerous cells which enable circulating tumors cells to migrate to and survive in distant sites. The recognition that some of these non-cancerous cells include key components of the immune system has re-ignited the field of immunotherapy in cancer. One particular area of immunotherapy research, tumor entrained neutrophils, will be reviewed in more depth. Ultimately, understanding the dynamic interplay between cancer cells and the metastatic niche offers fertile ground for progress both in the treatment and prevention of metastasis. ... Read more

Towards the Goal of Personalized Medicine in Gastric Cancer -- Time to Move Beyond HER2 Inhibition. Part II: Targeting Gene Mutations and Gene Amplifications and the Angiogenesis Pathway

Abstract: Gastric cancer is the second leading cancer cause of death globally. Apart from the successful targeting of HER2 over-expression in gastric cancer (GC) with trastuzumab, other targeted therapies in GC have fallen short or still in early clinical development. While HER2 over-expression accounts for up to 20% of GC, other potential actionable driver mutations occur at a much lower frequency in GC. In this review we describe some of the more interesting genetic aberrations including driver mutations in gastric cancer that have very potent inhibitors against them already in clinical development. Part I of this review will concentrate on the receptor tyrosine kinase (RTK) gene amplification (HER2, FGFR2, MET, EGFR). Part II will concentrate on gene mutations (HER2, KRAS, PIK3CA, BRAF) and gene rearrangement (ROS1, BRAF, HER2). Because of the low frequency of these potential driver mutations, perseverance in screening for these mutations will be needed in order to enroll enough of each uniquely molecularly defined subset of GC in order to demonstrate significant clinical benefit in a unique molecularly targeted therapy trial. This approach has been successfully employed in the clinical approval of crizotinib for the treatment of ALK-rearranged non-small cell lung cancer. Finally, we discuss a paradigm shift in the personalized treatment of GC patients where multiplex comprehensive screening of all GC patients for all these potential driver mutations simultaneously is performed to achieve efficiencies and timeliness in diagnosis and allowing enrollment into different molecularly targeted therapy trials and the prospective discovery of novel yet unknown actionable driver mutations. ... Read more

Towards the Goal of Personalized Medicine in Gastric Cancer -- Time to Move Beyond HER2 Inhibition. Part I: Targeting Receptor Tyrosine Kinase Gene Amplification

Abstract: Gastric cancer is the second leading cancer cause of death globally. Apart from the successful targeting of HER2 over-expression in gastric cancer (GC) with trastuzumab, other targeted therapies in GC have fallen short or still in early clinical development. While HER2 over-expression accounts for up to 20% of GC, other potential actionable driver mutations occur a much lower frequency in GC. In this review we describe some of the more interesting genetic aberrations including driver mutations in gastric cancer that have very potent inhibitors against them already in clinical development. Part I of this review will focus on the receptor tyrosine kinase (RTK) gene amplification (HER2, FGFR2, MET, EGFR). Part II will devoted to gene mutations (HER2, KRAS, PIK3CA, BRAF) and gene rearrangement (ROS1, BRAF, HER2). Because of the low frequency of these potential driver mutations, perseverance in screening for these mutations will be needed in order to enroll enough of each uniquely molecularly defined subset of GC in order to demonstrate significant clinical benefit in a unique molecularly targeted therapy trial. This approach has been successfully employed in the clinical approval of crizotinib for the treatment of ALK-rearranged non-small cell lung cancer. ... Read more

Nuclear Mode of the EGFR Signaling Network: Biology, Prognostic Value, and Therapeutic Implications

Abstract: Epidermal growth factor receptor (EGFR) belongs to a large family of receptor tyrosine kinases that mediates many important physiological processes in both normal and cancerous cells. EGFR is best known for its classical role as a plasma membrane-bound receptor that, upon binding to its ligands, recruits and phosphorylates downstream molecules which subsequently regulate protein functions, protein-protein interactions, and gene expression. Built upon this traditional view of the EGFR pathway, a number of therapeutic agents have been developed aiming to target EGFR by blocking ligand-mediated receptor activation or by inhibiting its kinase activity. Unfortunately, most of these interventions have yielded disappointing clinical results in the majority of cancer types evaluated, with the exception of non-small cell lung cancer that carries specific EGFR mutants. Given the notion that these EGFR mutations are absent or very rare in other cancer types, extensive investigations have been directed at other potential mechanisms. Some of these efforts have led to rationales for EGFR-based combination regimens; however, they also demonstrated limited clinical benefits. In this review, we will focus on an emerging line of research that examines a novel mode of EGFR signaling that takes place in the cell nucleus. Specifically, we will outline the findings from a number of reports that have together established nuclear EGFR to be a functionally diversified molecule that regulates the biology of normal and malignantly transformed cells. In light of the fact that the impact of nuclear EGFR on anti-cancer therapy has recently developed into an area of intensive investigations, this review will also summarize the results of these investigations that suggest a potential role the nuclear EGFR may play in tumor response to radiation, chemotherapy, and EGFR-targeted therapy. ... Read more

Treatment of Ovarian Cancer by Monoclonal Antibodies

Abstract: Despite the recent advances in its management using cytoreductive surgery and chemotherapy, ovarian cancer remains the most lethal gynecological malignancy. One possible treatment strategy that may improve patient outcome is the use of monoclonal antibodies (mAb) that selectively target tumor cells expressing tumor-associated antigens, and thus offer potential benefits such as avoiding the cytotoxic side effects in normal tissue caused by traditional chemotherapeutic agents. Based on the promising results of preclinical studies, various mAb are currently being evaluated in patients with ovarian cancer. Some of them have already demonstrated favorable clinical outcomes in phase I/II studies. However, in contrast to its use for hematological malignancies and certain solid malignancies such as breast and colorectal cancer, mAb-based therapy has not been convincingly proven to be clinically effective in patients with ovarian cancer. As the preclinical results of mAb's therapeutic effects on ovarian cancer have been encouraging, further investigations are needed to establish a more effective, specific, and less toxic treatment strategy for this malignancy. ... Read more

Adherence to Targeted Oral Anticancer Medications

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

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