EGFR-Targeted Therapeutics: Focus on SCCHN and NSCLC

Cancers of the head and neck and of the lung are associated with high morbidity and mortality rates that have remained relatively unchanged for more than 3 decades, despite advances in radiation therapies and chemotherapies over the same time. It is generally believed that the efficacy of standard therapy regimens has reached a plateau for these cancers. The discovery of specific aberrant molecular signaling pathways in solid tumors has afforded promising new directions for newer “targeted” cancer therapeutics. Among these, the epidermal growth factor receptor (EGFR) shows promise as a therapeutic target. Clinical studies have demonstrated that this targeted approach provides clinically meaningful benefit. This article reviews EGFR-targeted therapies in use and in development, with a focus on the role of EGFR in the pathophysiology of head and neck and lung cancer, and new concepts being investigated to improve outcomes with these agents

Concomitant Radiotherapy and Chemotherapy for High-Risk Nonmelanoma Skin Carcinomas of the Head and Neck

Background. To report on the use and feasibility of a multimodality approach using concomitant radiotherapy and chemotherapy in patients with high-risk nonmelanoma skin carcinoma (NMSC) of the head and neck. Methods. Records of patients with NMSC of the head and neck who received concomitant CRT at the University of North Carolina between 2001 and 2007 were reviewed. Results. Fifteen identified patients had at least one of the following high-risk factors: T4 disease (93%), unresectability (60%), regional nodal involvement (40%), and/or recurrence (47%). Ten patients were treated in the definitive setting and five in the postoperative setting. Platinum based chemotherapy was given in 14 (93%) patients. Ten of fifteen (67%) patients completed all planned chemotherapy treatments, and thirteen patients (87%) completed at least 80% of planned chemotherapy. Mild radiation dermatitis occurred in all patients and reached grade 3 in 13% of patients. No patients experienced grade 4 or 5 toxicity. With a median followup of 31 months in surviving patients, the 2-year actuarial locoregional control and relapse-free survival were 79% and 49%, respectively. Conclusions. Definitive or postoperative chemoradiotherapy for patients with locally advanced or regionally metastasized NMSC of the head and neck appears feasible with acceptable toxicities and favorable locoregional control

Developing Targeted Therapy against Pancreatic Cancer

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ENHANCING RADIATION SENSITIVITY IN NON-SMALL CELL LUNG CANCER

Lung cancer is the leading cause of cancer-related death. While radiation therapy is one of the standard treatments for lung cancer, the disease outcome after radiotherapy is still far from satisfactory despite ongoing advances in radiation techniques. Enhancing the radiosensitivity of lung cancer has the potential to improve the disease outcome of radiation treatments. Using a novel high throughput radiation sensitizing screen, previous work in the lab has identified several potent radiation sensitizers. The focus of my dissertation is on two of the identified pathways, HSP90 and MEK, using the potent and clinically relevant inhibitors ganetespib and trametinib. Using both in vitro experiments in multiple non-small cell lung cancer (NSCLC) cell lines and in vivo experiments in animal models, I tested the ability of these inhibitors to radiosensitize lung tumors in the clinically relevant context of chemoradiation. I have found that ganetespib sensitized lung cancer cells to radiation through attenuating DNA damage repair through attenuating DNA damage repair and accentuating G2-M cell cycle arrest. However, when combined with chemoradiation in vivo, ganetespib has variable effects on different cells. For radiation sensitization through MEK inhibition, I found that trametinib selectively sensitized KRAS-LKB1 co-mutant NSCLC, but not KRAS-TP53 mutant cells, through radiation-induced senescence. In the LKB1 wild type background, trametinib and radiation activated AMPK-autophagy pathway to rescue cells from senescence, therefore conferring resistance to the radiosensitization. In summary, my studies which focused on how these two specific targeted pathways caused radiation sensitization emphasized the need to better understand the molecular and signaling complexities in determining radiation sensitization effects especially when multiple modalities are combined. Preclinical studies in the context of clinically relevant treatment settings are warranted for optimal clinical translation and personalized cancer therapy

Adjuvant Treatment in Pancreatic Cancer: Shaping the Future of the Curative Setting

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease even in the early stages, despite progresses in surgical and pharmacological treatment in recent years. High potential for metastases is the main cause of therapeutic failure in localized disease, highlighting the current limited knowledge of underlying pathological processes. However, nowadays research is focusing on the search for personalized approaches also in the adjuvant setting for PDAC, by implementing the use of biomarkers and investigating new therapeutic targets. In this context, the aim of this narrative review is to summarize the current treatment scenario and new potential therapeutic approaches in early stage PDAC, from both a preclinical and clinical point of view. Additionally, the review examines the role of target therapies in localized PDAC and the influence of neoadjuvant treatments on survival outcomes