Current Cancer Drug Targets - Volume 4, Issue 8, 2004

Highly specific signal transduction inhibitors are being developed as anti-cancer agents against an array of molecular targets, with the promise of increased selectivity and lower toxicity than classic cytotoxic chemotherapy agents. Rapamycin and its analogues are a promising class of novel therapeutics that specifically inhibit signaling from the serine-threonine kinase, mammalian target of rapamycin (mTOR). mTOR is a key intermediary in multiple mitogenic signaling pathways and plays a central role in modulating proliferation and angiogenesis in normal tissues and neoplastic processes. Rapamycin potently inhibits T-cell proliferation, and is approved for clinical use as an immuno-suppressant following kidney transplantation. Hyperactivation of mTOR signaling has been implicated in tumorigenesis, and promising pre-clinical studies in several tumor types suggest that the anti-proliferative and anti-angiogenic properties of rapamycin may be useful in cancer therapy. These studies have led to several clinical trials evaluating the safety and efficacy of rapamycin analogs in cancer therapy. The goal of this article is to review the mechanism of action of rapamycin as an anti-cancer agent, and to review the clinical experience with rapamycin and rapamycin analogs as immunosuppressive and anti-neoplastic therapeutic agents.

Head and neck cancer, the sixth most common type of cancer worldwide, is associated with a dismal prognosis that has minimally improved during the last few decades. Future advances in the treatment and prognosis of this fatal disease largely rely upon a better understanding of the molecular events that underlie tumor development and progression, allowing specific targeting of the involved molecules and pathways. In this context, recent efforts have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins comprise a family of latent cytoplasmic transcription factors that become transiently activated in response to extracellular signals, leading to regulation of diverse physiological responses. There is compelling evidence that persistent activation of specific STAT molecules, especially Stat3 and Stat5, possesses oncogenic properties in a number of human cancers, including head and neck cancer. The presence of constitutively activated STAT molecules in cancer cells is mainly attributed to the dysregulation of upstream activating pathways and the aberration of negative regulatory mechanisms. The end result is induction of specific target genes that stimulate cell proliferation, prevent apoptosis, promote angiogenesis and facilitate tumor immune evasion. Therefore, targeting and disruption of oncogenic STAT signaling may theoretically be accomplished through various approaches, involving direct (e.g. interference with the various facets of STAT expression, activation or function) and indirect strategies (e.g. inhibition of upstream signaling events and enhancement or restoration of negative regulatory mechanisms). The availability of multiple potential targets for interruption of aberrant STAT signaling in cancer and the thus-far promising results have generated optimism for the clinical applicability of STAT targeting in head and neck cancer, which is the focus of this review.

Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator β-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. Deregulation of the canonical Wnt/β-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or oncogenic mutations of β-catenin, has been implicated in colorectal tumorigenesis. Although oncogenic mutations of β-catenin have only been discovered in a small fraction of non-colon cancers, elevated levels of β- catenin protein, a hallmark of activated canonical Wnt pathway, have been observed in most common forms of human malignancies, indicating that activation of this pathway may play an important role in tumor development. Over the past 15 years, our understanding of this signaling pathway has significantly improved with the identification of key regulatory proteins and the important downstream targets of β-catenin/Tcf transactivation complex. Given the fact that Wnt/β-catenin signaling is tightly regulated at multiple cellular levels, the pathway itself offers ample targeting nodal points for cancer drug development. In this review, we discuss some of the strategies that are being used or can be explored to target key components of the Wnt/β- catenin signaling pathway in rational cancer drug discovery.

Colon, breast and lung adenocarcinomas - three of the major malignancies occurring in humans, together with ovarian, endometrial, kidney and liver adenocarcinomas, account for more then 50% of cancerrelated death. As the number of cancer-related deaths has not decreased in recent years, major efforts are being made to find new and more specific drugs for cancer treatment. One of the approaches developed in recent years for targeted cancer therapy is the construction and use of chimeric proteins. Chimeric cytotoxins are a class of targeted molecules designed to recognize and specifically destroy cells over-expressing specific receptors. These molecules, designed and constructed by gene fusion techniques, comprise both the cell-targeting and the cell-killing moieties. Our laboratory has developed a number of chimeric proteins based on an analog of Gonadotropin Releasing Hormone (GnRH) as their targeting moiety. These chimeras recognize a GnRH-binding site that, we found, was over-expressed on a surprisingly wide variety of cancers, all confined to the adenocarcinoma type. A GnRH analog was fused to a large number of killing moieties, including bacterial or human pro-apoptotic proteins. All GnRH-based chimeric proteins selectively killed adenocarcinoma cells both in vitro and in vivo. Utilizing GnRH-based chimeric proteins for targeted therapy could open up new vistas in the fight against adenocarcinomas in humans. This review summarizes the latest developments in the area of targeted cancer therapy via specific antigens/receptors, as well as our latest findings in targeting GnRH-binding sites using GnRH-based chimeric proteins for specific and targeted adenocarcinoma therapy in humans.

Patients with advanced solid tumors frequently relapse and succumb to their metastatic disease after developing resistance to conventional treatment modalities such as chemotherapy and radiotherapy. In these patients, novel strategies of targeting widespread tumors are urgently needed. The increasing knowledge of the underlying pathogenetic mechanisms has led to the identification of numerous molecules that are overexpressed in various tumors and accumulate at the cell surface. The use of genetically modified bacteria and their toxins targeting these surface molecules has emerged as a promising new treatment strategy in refractory cancers. This review focuses on bacterial toxins such as Diphtheria toxin (DT), Pseudomonas exotoxin A (PE) and Clostridium perfringens enterotoxin (CPE). In addition, the use of anaerobic bacteria such as Clostridium, Salmonella and Bifidobacterium spp. as drug-delivery systems targeting hypoxic tumor areas will be discussed as a new therapeutic modality of advanced solid tumors.