Drugs in preclinical and early-stage clinical development for pancreatic cancer

INTRODUCTION: Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the US and Europe, and the lethality of this cancer is demonstrated by the fact that the annual incidences are approximately equal to the annual deaths. Current therapy for PC is multimodal, involving surgery and chemotherapy. Clinical symptoms are unspecific, and consequently about 85% of patients with PC are diagnosed at advanced tumor stages without any surgical therapy options. Since the therapeutic rates for PC are so dismal, it is essential to review the clinical targets for diagnosis and treatment of this lethal cancer. AREAS COVERED: In this review, we discuss potential treatment options for PC by identifying molecular targets including those involved in cell proliferation, survival, migration, invasion and angiogenesis. Targeting these molecules in combination with surgery could improve the clinical outcome for PC patients. EXPERT OPINION: For a decade, gemcitabine has remained the single first-line chemotherapeutic agent for advanced adenocarcinoma of the pancreas; however, less than 25% of patients benefit from gemcitabine. The reason for frequent reoccurrence of PC after conventional methods such as surgery, radiation and/or chemotherapy is due to the lack of understanding of the basic underlying metabolic cause of the cancer and thus consequently remains uncorrected. Our understanding of drug resistance in PC is still not clear and may be answered by focusing on new useful biomarkers and their role in chemo- and radioresistance.     

New drugs in advanced non-small-cell lung cancer: searching for the correct clinical development

Importance of the field: Non-small-cell lung cancer (NSCLC) is one of the most active fields of research in oncology, with many drugs under clinical development. Most of these drugs offer novel mechanisms of action compared with drugs currently used in clinical practice.

Areas covered in this review: In this article, results recently obtained with most promising new drugs for advanced NSCLC are briefly described.

What the reader will gain: Most of the new drugs are currently being tested without a biomarker-driven selection, due to inadequate knowledge of predictive factors. A few drugs are tested in biologically selected samples of NSCLC patients. The results obtained with crizotinib in patients with ALK gene rearrangement are a good example of the speed with which biological discoveries can be translated to clinical testing.

Take home message: Emerging clinical and molecular data demonstrate that NSCLC is a family of related but distinct diseases. Some drugs tested in unselected population will probably obtain an incremental benefit compared to the current standard, but this will not substantially change the unfavorable prognosis of NSCLC patients. By contrast, unprecedented and much more cost-effective results can be obtained when targeted agents are administered following appropriate biomarker-driven patient selection.     

Novel treatments and therapies in development for pancreatic cancer

Until recently, 5-fluorouracil was the most widely used treatment for non-resectable pancreatic cancer. This treatment, however, only resulted in a median survival time of approximately 4 months. In the last few years, gemcitabine has rapidly become the new treatment benchmark, due more to its superior clinical benefit rather than to it conferring an increased median survival (approximately 5-6 months). Thus, the outlook for patients with pancreatic cancer is still relatively bleak. A number of new treatment options are presently being investigated. Some of these are combination therapies involving gemcitabine and other chemotherapeutic agents or radiation. Other novel treatment strategies are also already being evaluated in clinical studies. Some of the more promising treatments in development are discussed and evaluated in this article.     

Novel treatments and therapies in development for pancreatic cancer

Until recently, 5-fluorouracil was the most widely used treatment for non-resectable pancreatic cancer. This treatment, however, only resulted in a median survival time of ~ 4 months. In the last few years, gemcitabine has rapidly become the new treatment benchmark, due more to its superior clinical benefit rather than to it conferring an increased median survival (～ 5 – 6 months). Thus, the outlook for patients with pancreatic cancer is still relatively bleak. A number of new treatment options are presently being investigated. Some of these are combination therapies involving gemcitabine and other chemotherapeutic agents or radiation. Other novel treatment strategies are also already being evaluated in clinical studies. Some of the more promising treatments in development are discussed and evaluated in this article.     

Novel antibodies targeting immune regulatory checkpoints for cancer therapy

Cancers must evade or suppress the immune system in order to develop. Better understanding of the molecular regulation governing tumour detection and effective activation of the immune system (so called immune regulatory checkpoints) has provided new targets for cancer immunotherapy. Therapeutic monoclonal antibodies against these targets are currently undergoing clinical evaluation with more in pre-clinical development; buoyed by the recent licence approval of the anti-CTLA-4 antibody, ipilumumab, for use in melanoma. This article will review the current status of the various antibodies and target molecules being investigated.     

TNP-470: an angiogenesis inhibitor in clinical development for cancer

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.     

TNP-470: an angiogenesis inhibitor in clinical development for cancer

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi’s sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m² with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.     

Erlotinib: early clinical development in brain cancer

Introduction: Glioblastoma (GBM) is the most common brain cancer in adults. It is also, unfortunately, the most aggressive type and the least responsive to therapy. Overexpression of EGFR and/or EGFRvIII is frequently found in GBM and is frequently associated with the more malignant phenotype of the disease and a poor clinical outcome. EGFR-targeted therapy represents a promising anti-GBM therapy. Two EGFR kinase inhibitors, gefitinib and erlotinib have been tested in clinical trials for malignant gliomas. However, the clinical efficacy of EGFR-targeted therapy has been only modest in GBM patients.

Areas covered: The authors provide an evaluation of erlotinib as a potential therapy for GBM. The authors highlight experiences drawn from clinical trials and discuss the challenges, which include the insufficient penetration through the blood–brain barrier (BBB) and chemoresistance.

Expert opinion: Malignant brain tumours have a very complex signalling network that is not only driven by EGFR. This complexity dictates tumour sensitivity to EGFR-targeted therapies. Alternative kinase signalling pathways may be involved in parallel with the inhibited target, so that a single target’s inactivation is not sufficient to block downstream oncogenic signalling. The use of nanocarriers offers many opportunities, such as the release of the drug to specific cells or tissues, together with the ability to overcome different biological barriers, like the BBB.     

New directions in the management of advanced pancreatic cancer: a review

Complete surgical resection is the only potentially curative option for pancreatic cancer. However, most patients have advanced/metastatic disease at the time of diagnosis, or will relapse after surgery. Systemic chemotherapy is only palliative. Gemcitabine-based therapy is an acceptable standard for unresectable locally advanced/metastatic pancreatic cancer, but average median survival is only 6 months. The addition of other chemotherapies (including other antimetabolites, platinum, and topoisomerase I inhibitors) or targeted therapies (farnesyl transferase inhibitors, metalloproteinase inhibitors, cetuximab and bevacizumab) to gemcitabine has failed to improve outcome. The combination of gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor of the human epidermal growth factor receptor, was recently approved by the US/European authorities for use in advanced disease. In a phase III trial, the combination demonstrated a significant improvement in overall survival compared with gemcitabine monotherapy. Positive efficacy results have also been observed in a phase III trial, favoring the addition of capecitabine to gemcitabine compared with gemcitabine alone. This review focuses on the recent developments in systemic treatment, and discusses how novel agents might be incorporated into future treatment strategies for pancreatic cancer.     

Akt inhibitors in clinical development for the treatment of cancer

Importance of the field: The evolution of targeted therapies is dependent upon identification of cellular moieties that can be pharmacologically modulated. As one such example, the serine-threonine kinase Akt was identified nearly two decades ago. Since then, its role in mediating multiple signaling cascades (ultimately leading to cell growth and proliferation) has since been identified. More recently, several agents have been developed that antagonize Akt – these agents are in various stages of clinical testing.

Areas covered in this review: Herein, we outline development of several promising Akt inhibitors, including perifosine, MK-2206, RX-0201, PBI-05204, GSK2141795 and others.

What the reader will gain: The reader will gain insight into the current pipeline of Akt inhibitors, and the degree to which these agents have been examined both clinically and preclinically.

Take home message: With an emerging pipeline of agents targeting Akt, it will be critical to decipher which amongst them holds the greatest promise. Herein, we explore this drug pipeline and provide strategies for determining the future clinical application of these agents.