Contents
Mammalian Target of Rapamycin (mTOR)
Inhibitors as Anti-Cancer Agents Pp.621-635
Ravi
D. Rao, Jan C. Buckner and Jann N. Sarkaria
Targeting the STAT Pathway in Head and Neck
Cancer: Recent Advances and Future Prospects Pp.637-651
N.G.
Nikitakis, H. Siavash and J.J. Sauk
Wnt/b-Catenin
Signaling Pathway as Novel Cancer Drug Targets Pp.653-671
Hue
H. Luu, Ruiwen Zhang, Rex C. Haydon, Elizabeth Rayburn, Quan Kang, Weike Si,
Jong Kyung Park, Hui Wang, Ying Peng, Wei Jiang and Tong-Chuan He
Surface Antigens/Receptors for Targeted
Cancer Treatment: The GnRH Receptor/Binding Site for Targeted Adenocarcinoma
Therapy Pp.673-687
R.
Eaveri, A. Ben-Yehudah and H. Lorberboum-Galski
Bacteria and Bacterial Toxins as Therapeutic
Agents for Solid Tumors Pp.689-702
P.
Michl and T.M. Gress
[Back to top]
Mammalian
Target of Rapamycin (mTOR) Inhibitors as Anti-Cancer Agents
Ravi D. Rao, Jan C. Buckner and Jann N. Sarkaria
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.
[Back to top] Targeting the STAT Pathway in Head and Neck
Cancer: Recent Advances and Future Prospects
N.G.
Nikitakis, H. Siavash and J.J. Sauk
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.
[Back to top] Wnt/b-Catenin Signaling Pathway as Novel Cancer
Drug Targets
Hue
H. Luu, Ruiwen Zhang, Rex C. Haydon, Elizabeth Rayburn, Quan Kang, Weike Si,
Jong Kyung Park, Hui Wang, Ying Peng, Wei Jiang and Tong-Chuan He
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 b-catenin, initiate a complex signaling
cascade that plays an important role in regulating cell proliferation and
differentiation. Deregulation of the canonical Wnt/b-catenin signaling pathway, mostly by
inactivating mutations of the APC tumor suppressor, or oncogenic mutations of b-catenin, has been implicated in colorectal
tumorigenesis. Although oncogenic mutations of b-catenin
have only been discovered in a small fraction of non-colon cancers, elevated
levels of b-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 b-catenin/Tcf transactivation complex. Given
the fact that Wnt/b-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/b-catenin signaling
pathway in rational cancer drug discovery.
[Back to top] Surface Antigens/Receptors for Targeted Cancer
Treatment: The GnRH Receptor/Binding Site for Targeted Adenocarcinoma Therapy
R. Eaveri, A. Ben-Yehudah and H. Lorberboum-Galski
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 cancer-related 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.
[Back to top] Bacteria and Bacterial Toxins as Therapeutic Agents
for Solid Tumors
P.
Michl and T.M. Gress
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.