Challenges in developing targeted therapy for pancreatic adenocarcinoma

Background: Pancreatic adenocarcinoma is a leading cause of cancer deaths in the US. Gemcitabine-based chemotherapy remains the cornerstone treatment for advanced pancreatic cancers. Research into the molecular pathogenesis of pancreatic cancers has allowed scientists to understand the complex heterogeneous signals associated with them. Targeting these pathways with chemical inhibitors could improve patient outcome. Objective: To describe the molecular heterogeneity typical of pancreatic cancers and to discuss targeted therapies in development, and the challenges facing these agents. Methods: We reviewed Pub Med. literature, clinical trial database (clinicaltrials.gov), American Society of Clinical Oncology (ASCO) and American Association of Cancer Research (AACR) websites. Conclusions: Molecular pathogenesis of pancreatic cancer involves multiple pathways and defined mutations. This molecular heterogeneity is a major reason for failure of targeted therapy. Targeting multiple oncogenic pathways using novel targeted therapies could improve patient survival.     

Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy

Introduction: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting.

Areas covered: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-β signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment.

Expert opinion: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a ‘precision medicine’ approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes.     

Understanding resistance to targeted cancer drugs through loss of function genetic screens

Comprehensive analysis of cancer genomes has provided important insights in the critical alterations that confer proliferation and survival advantage to the tumor, so-called driver mutations. Tumors harboring these genetic changes frequently exhibit striking sensitivities to inhibition of these oncogenic driver pathways, a principle referred to as oncogene addiction. Substantial progress has been made in the development of drugs that specifically target components of the pathways that are associated with these driver mutations. This has enabled the first steps in a shift from the use of cytotoxic drugs to highly selective targeted therapeutic agents for the treatment of cancer. Unfortunately, despite the expanding development of targeted anti-cancer strategies, treatment failure due to primary or acquired resistance is still an almost inevitable outcome in most advanced human cancers. Understanding drug resistance mechanisms will help design more efficient combination treatment strategies that help block resistance mechanisms before they become clinically manifest. In this review, we discuss how RNA interference functional genetic screens can be used to identify clinically relevant mechanisms of drug resistance and how this technology can be used to develop effective combination therapies.     

Emerging insights into resistance to BRAF inhibitors in melanoma

Melanoma is the most aggressive form of skin cancer. The treatment of patients with advanced melanoma is rapidly evolving due to an improved understanding of molecular drivers of this disease. Somatic mutations in BRAF are the most common genetic alteration found in these tumors. Recently, two different mutant-selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, have gained regulatory approval based on positive results in randomized phase III trials. While the development of these agents represents a landmark in the treatment of melanoma, the benefit of these agents is limited by the frequent and rapid onset of resistance. The identification of several molecular mechanisms of resistance to BRAF inhibitors is rapidly leading to the clinical testing of combinatorial strategies to improve the clinical benefit of these agents. These mechanisms, and the lessons learned from the initial testing of the BRAF inhibitors, provide multiple insights that may facilitate the development of targeted therapies against other oncogenic mutations in melanoma, as well as in other cancers.     

Novel targeted treatment options for advanced cholangiocarcinoma

Introduction: Surgical resection remains the mainstay of potentially curative treatment in the early stages of cholangiocarcinoma, whereas for the advanced stage, systemic chemotherapeutics and experimental targeted therapies are the primary treatment options. The molecular heterogeneity of the tumor is based on location, liver dysfunction, and relative rarity of the disease and confers challenges for clinical trial enrollment. The advancements in the understanding of molecular pathogenesis of cholangiocarcinoma have led to the development of targeted therapies that are currently being evaluated in the clinical trials.

Areas covered: This review summarizes the current understanding and future directions of targeted therapeutic options in the management of advanced cholangiocarcinoma.

Expert opinion: Advanced cholangiocarcinoma has a dismal prognosis; improved understanding of the molecular pathogenesis and advancements in development of targeted therapy offers hope that we may improve outcomes in this rare, but highly lethal cancer. Among the newly discovered molecular alterations, targeting FGFR2 fusions, IDH1/2 mutations and HER2 receptors hold great promise for improving the future management of cholangiocarcinoma. Immunotherapy in combination with targeted agents and chemotherapy may improve outcomes. In addition, drugs targeting the MEK, EGFR, KRAS, BRAF, and ROS1 pathways and neo-angiogenesis may also provide new horizons in the management of cholangiocarcinoma.     

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition.

Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field.

Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver' mutations and optimization of personalized therapies are needed.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements.

Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment.

Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.     

Targeting heat shock response pathways to treat pancreatic cancer

Pancreatic cancer belongs to the group of extremely aggressive human cancers; conventional cancer treatments have little impact. Increasing understanding of the pathways associated with pancreatic cancer progression has enabled the development of targeted therapy on this cancer. Heat shock proteins (HSPs) and related heat shock response (HSR) pathways control multiple important oncogenic pathways for pancreatic cancer development. Consequently, they represent promising novel targets for pancreatic cancer therapy. Various strategies have been proposed and elaborated to target HSPs/HSR in pancreatic cancer with the corresponding modulators, the details of which are highlighted in this review.     

Malignancies of the head and neck: the role for molecular targeted agents

Although cancers arising in the head and neck region are a diverse group of malignancies, a unifying thread remains a poor overall survival for patients with advanced, recurrent or metastatic disease. Treatment strategies need to evolve and improve upon established therapeutic practices. As the process of cancer evolution is understood to be derived from aberrations in genetic and epigenetic processes, molecularly targeted agents offer attractive therapeutic options by restoring normal control of oncogenic processes. The direct role for the treatment of squamous cell carcinoma of the head and neck, nasopharynx and salivary gland carcinomas with these novel, molecularly targeted agents are reviewed and their potential to improve on the existing standard of care is further explored.     

The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer

Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation.

Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in early phase I studies.

Expert opinion: Among the several NTRK-inhibitors, entrectinib and LOXO-101 are those in more advanced stage of clinical development. Both agents have shown encouraging activity along with a tolerable safety profile in patients with different solid tumors harboring NTRK-fusions, emerging as new promising therapeutic options for molecularly selected patients with advanced Trk-driven lung cancers. Results from ongoing phase II basket trials are eagerly awaited.     

Advanced or metastatic pancreatic cancer: molecular targeted therapies

Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. However, clinical developments over the past decade have been modest and advances are incremental at most. The core drug and the backbone of treatment in all settings of pancreatic adenocarcinoma-adjuvant, locally advanced, and metastatic-remains gemcitabine. The past decade of research focused initially on combining cytotoxic therapies with gemcitabine, and during that time a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis, and resistance to apoptosis. This research is of particular importance, as data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated marginal survival benefit in combination with gemcitabine in phase III clinical trials. Even though the failures of targeted therapies in the clinical setting are discouraging, it is reasonable to surmise that major progress will evolve as the molecular biology of pancreatic adenocarcinoma continues to be unraveled. This review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials.     

Emerging drugs for squamous cell lung cancer

Introduction: The management of advanced NSCLC has been shifted by histology-driven treatment and molecularly targeted therapy, especially in lung adenocarcinoma. However, as the second most common histology in NSCLC, the treatment options for squamous cell lung cancer (SQCLC) remain very limited.

Areas covered: The review first discusses the role of histology in management of NSCLC and new cytotoxic agents in SQCLC, and then addresses genomic characterization and potential molecular targets in SQCLC. The article then provides an overview for several major categories of novel molecularly targeted therapies and immune-based strategies with particular attention to ongoing SQCLC trials.

Expert opinion: The key challenges in drug development are to uncover novel actionable targets and to identify predictive biomarkers. Progress in genomic analysis has identified some promising targetable genes and oncogenic pathways in SQCLC with a wave of targeted agents being tested in clinical trials. Immunotherapy has also raised great interest in management of SQCLC, especially agents targeting immune check points, cytotoxic T-lymphocyte antigen-4, programmed death-1 receptor and its ligands. Better understanding of tumor biology and development of novel targeted therapies will help to facilitate more effective personalized therapy for patients with this devastating illness.     

Novel targeted therapies for the treatment of penile cancer

Introduction: The treatment of penile cancer has changed over the past decade in that it was primarily a surgically managed disease and those with locally advanced or metastatic disease uniformly had a very poor prognosis. However, with the use of better traditional systemic chemotherapeutic agents in the neoadjuvant and adjuvant settings, the disease-specific survival and general outlook has improved. However, there is still a large group of patients who will progress even while on systemic therapy. It is in those patients where the application of targeted therapies has been investigated with some experiencing partial or even complete responses. With the improvement seen in patients with chemotherapy refractory disease, the application of novel targeted agents in the neoadjuvant setting may have a resultant positive impact on patient survival.

Areas covered: This review includes research pertaining to targeted therapies, biomarkers and signaling pathways involved with penile cancer. The article was based on a literature search using the keywords ‘penile cancer’ and ‘targeted therapies’.

Expert opinion: Penile cancer at the advanced stages of the disease has a high mortality. The utilization of novel targeted therapies in these situations is warranted in combination with, or sequentially with, traditional cytotoxic chemotherapy to improve the patient survival rate. Personalized therapy is nearly here for penile cancer and should be made real within the next decade.     

Emerging drugs in endometrial cancers

Importance of the field: Endometrial cancer remains the most common gynecologic malignancy. The treatment of endometrial cancer is rapidly evolving.

Areas covered in this review: In this article, we aim to review current and future treatment options in the medical treatment of endometrial cancers.

What the reader will gain: The cornerstone of curative therapy for patients with endometrial cancer is surgical treatment. Cytotoxic chemotherapy is the mainstay of therapy for metastatic and advanced endometrial cancer. The most active chemotherapy agents are anthracyclines, platinum compounds and taxanes. Combination chemotherapy has produced higher response rates than single agent therapy. Cisplatin and doxorubicin combination chemotherapy has served as the control arm in many trials. Three-drug combination regimen has shown the highest response rate but with increased toxicity. Despite the lack of published data supporting the superiority of the paclitaxel plus carboplatin combination over doxorubicin and cisplatin, many centers prefer this regimen as a standard of care. Hormonal therapy should be considered in patients with low grade tumors and in those with a poor performance status. Recent advances in the understanding of the molecular biology of endometrial cancer have led to development of targeted therapies. Among these the more promising ones are mTOR inhibitors and antiangiogenic agents.

Take home message: Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve outcome for women with endometrial adenocarcinomas.     

Stratified medicine for cancer therapy

As knowledge of the biological processes underlying malignant transformation becomes increasingly sophisticated, apparently similar diseases can be redefined according to the critical disrupted biological pathways and networks. The key genetic changes in most cancers can be mapped to one of a relatively few pathways, making it possible to classify tumours by their abnormal pathways and to identify potentially treatable--'druggable'--targets within these. The aim of the stratified approach to cancer therapy is to improve the effectiveness, tolerability and affordability of novel therapeutic agents.     

Recent advances in Hsp90 inhibitors as antitumor agents

One promising therapeutic strategy for treating cancer is to specifically target signal transduction pathways that have a key role in oncogenic transformation and malignant progression. Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. It is responsible for modulating cellular response to stress by maintaining the function of numerous signalling proteins - known as 'client proteins' - that are associated with cancer cell survival and proliferation. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Small molecule Hsp90 inhibitors bind to the ATP binding pocket, inhibit chaperone function and could potentially result in cytostasis or cell death. Consequently, many client proteins are targeted for degradation via the ubiquitin-proteasome pathway including receptor and non receptor kinases (Erb-B2, epidermal growth factor receptor, and Src family kinases), serine/threonine kinases (c-Raf-1 and Cdk4), steroid hormone receptors (androgen and estrogen), and apoptosis regulators such as mutant p53. Inhibition of Hsp90 function has also proven effective in killing cancer cells that have developed resistance to targeted therapies such as kinase inhibitors. This review is intended to update recent developments in new Hsp90 inhibitors as antitumors agents, the design, biological evaluation and their clinical trials studies.