Review
Signal transduction therapy of cancer

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Abstract

Signal transduction therapy for cancer targets signaling elements with key roles in cancer cell survival and proliferation, but with more minor roles in the survival of healthy cells. Cancer cells have shrunken signaling networks, and therefore tend to be dependent on fewer signaling modules than non-cancerous cells. Thus, targeted therapy holds the promise of efficacy with minimal toxicity. Yet, with the notable exception of Gleevec for the treatment of early chronic myelogenous leukemia (CML), targeted therapies have so far had minimal success. Unlike early CML, which is dependent upon BCR-ABL, most cancers are not dependent on a single survival factor. Furthermore, tumors are constantly evolving entities, and are heterogeneous in their cellular makeup, compounding the challenge. “Smart cocktails”, comprising rational combinations of therapies, need to be developed to meet this challenge. What are the best pathways to target, and why? What types of molecules can be developed into effective therapeutics? What combinations are likely to be successful? Here we present an overview of the principles that need to be considered in designing effective targeted therapy for cancer.

Section snippets

Preface

In December 1971, when President Nixon signed the National Cancer Act, the United States started to fight cancer in an organized fashion. Since then, federal governments have invested more than 100 billion dollars in programs to fight, detect and prevent cancer. This act of the US government stimulated other non-profit organizations within the United States and worldwide to fund research on cancer. Many pharmaceutical companies have started to develop anti-cancer therapies, and today much of

General considerations

Cancer is a collection of over 100 diseases afflicting all body organs. Even a single type of cancer presents itself differently in different individuals. The disease is a malfunction of the biochemical networks and signaling networks that drive the normal cell. With time the cell accumulates mutations and epigenetic changes, which alter the signaling and biochemical networks. Certain combinations of these alterations lead to cell transformation and cancer.

The incidence of cancer is low but

Signal transduction as a platform for drug discovery

Signal transduction describes the conversion of external signals, generated by hormones, growth factors, neurotransmitters, chemokines, cytokines and even small molecules such as ATP, to a biochemical response, leading to a cellular response. These responses can lead to alterations in metabolism, gene expression, cell division, and cell death. The process can begin at the cell membrane or within the cell, leading to an array of biochemical reactions, depending on the signaling system. The

Target and drug evaluation using pre-clinical tumor models

The shift from cytotoxic chemotherapy to targeted signal transduction therapy necessitates a paradigm shift in the design of pre-clinical drug assessment strategies. In the quest for rationally developed drugs, target validation is a critical step towards verifying a purported mechanism of action. After a compound has been shown to inhibit the action of an oncoprotein such as a protein tyrosine kinase (PTK), one needs to find a cell line for which proliferation and/or survival depend on the

Protein kinase inhibitors

Protein phosphorylation is the most frequent post-translational modification of proteins and is intimately involved with many signal transduction processes. It is believed that at least one third of cellular proteins are phosphorylated and as a consequence they change their biochemical activities. Many of the 518 protein kinases are Ser/Thr kinases and only 91 are protein tyrosine kinases (PTKs). The 91 PTKs and a subset of Ser/Thr kinases are involved in cellular signaling. These signaling

Specific protein kinase targets and their targeting agents

In this section we shall focus on signaling pathways regulated by protein kinases. The signaling inhibitors discussed are mainly low molecular weight compounds and antibodies.

Targeting chaperone proteins: Hsp90 inhibitors

Chaperone proteins maintain the conformation, stability, activity and cellular localization of client proteins, many of which are involved in oncogenic signaling. Oncogenic proteins that require chaperones include c-Src, Bcr-Abl, Her2, C-Raf, B-Raf, CDK4, PKB/Akt, steroid hormone receptors, mutant p53, HIF1α, survivin and telomerase (hTERT). Because these oncogenic products require chaperone activity for correct folding and activity, the cancer cell is “addicted” to their chaperones, most

Proteasome inhibitors

Cancer cells are more sensitive than normal cells to proteasome inhibitors. This is probably because protein synthesis in cancer cells depends on the supply of amino acids generated by the degradation of proteins by the ubiquitin–proteasome system (Mizrachy-Schwartz and Levitzki, personal communication). Multiple myeloma (MM) cells show the highest sensitivity to proteasome inhibition. Proteasome inhibitors block IκB degradation and therefore attenuate NFκB signaling, on which MM cells depend

Targeting Bcl2 family proteins: BH3 mimetics

Bcl2 family proteins play a key role in the anti-apoptotic shield many leukemias and solid tumors develop. Bcl2 and its family members – BclXL, Bclw and Mcl-1– bind to the BH3 domains of pro-apoptotic proteins, thus preventing them from executing their pro-apoptotic activities. A number of agents that bind to the protein surfaces of the Bcl2 family proteins have been developed and shown to inhibit their anti-apoptotic effects. Thus, ABT 737 (Oltersdorf et al., 2005) was found to block Bcl2-

Targeting transcription as a therapeutic modality

Several of the best-selling therapeutic agents on the US market target transcription factors (TFs). All were discovered by targeting pathological phenotypes, and only later were they found to actually target TFs. Drugs that prevent transcription include: Cyclosporin A, an anti-inflammatory agent targeting nuclear factor of activated T cells (NF-AT); thiazolidinediones, which target Peroxisome Proliferator Activated Receptor γ (PPARγ) for the treatment of diabetes type 2 and the estrogen

Epigenetic therapy

The initiation and the progression of cancer are regulated by both genetic and epigenetic events. Epigenetic events, unlike genetic events, are in principle reversible. Epigenetic events include methylation and acetylation. Methylation occurs on DNA, modulating directly gene expression. Acetylation is well recognized on histones, modulating chromatin structure, also leading to modulation of gene expression. Acetylation can occur on many proteins that carry out vital functions within the cell.

Targeting angiogenesis

Solid tumors are composed of two interdependent compartments, the malignant cells and the tumor micro-environment, which includes the extracellular matrix, stromal cells and blood vessels. Inhibition of the stromal components that sustain the tumor is a valid strategy, if one can limit the toxic effects. One important target is angiogenesis, i.e. the formation of new blood vessels.

Immunotherapy of cancer

Cancer immunotherapy encompasses the use of specific antibodies against defined molecular targets, as well as recruitment and augmentation of the natural anti-tumor immune response. The aim of cancer immunotherapy is to harness the unique power of the immune system to hunt down cancer cells and destroy them.

DNA and RNA-based therapies

Gene therapy involves the use of nucleic acids for therapeutic purposes. The NIH registry of clinical trials (http://clinicaltrials.gov) lists more than 100 ongoing gene therapy trials for the treatment of cancer. Strategies for gene therapy for cancer include augmentation of tumor suppressors and inactivation of oncogenes. The major hurdle to effective gene therapy is delivery. Trials have been conducted mostly in cancers that tend to be localized and therefore lend themselves to local or

Resistance to therapy

We have outlined how signal transduction therapy is expected to have a major impact on cancer therapy. Nonetheless, serious problems remain, especially the development of resistance. As we have mentioned previously in this article, even tumors that are initially sensitive to a targeted therapy, generally develop resistance. This can be due to a mutation in the targeted molecule itself, as in the case of the so-called “gatekeeper” mutations in BCR-ABL that prevent Gleevec from binding. Analogous

Combination therapy

As discussed above, even tumors that are initially sensitive to a targeted therapy eventually become resistant, due to mutations in the target and/or due to bypass of the targeted pathway. “Smart cocktails” of therapeutic combinations are being designed, to reduce the probability of resistance emerging.

Synthetic lethality

The success of combination therapy is actually based on the cooperation of two (or more) gene products to assure cell survival. Whereas inhibiting the function of each gene product alone may have no effect or a weak effect, the inhibition of both induces lethality. These two genes are then considered to be “synthetically lethal” (Kaelin, 2005). Thus, if one knows the genetic lesions in a cancer cell one can, in principle, search for the genes within the cancer cells whose silencing will lead to

Conclusions

The last four decades following the 1971 anti-cancer act have seen tremendous progress in the war against cancer. Although the achievements in the clinic are not so dramatic so far, the path one needs to follow is becoming clearer. We all understand that for cancer therapy to succeed we need to develop biomarkers that will allow matching of the anti-cancer agents with the biochemical profile of the tumor. We also understand that we need to view the tumor as an organ in intimate interaction with

Levitzki has pioneered signal transduction therapy, especially in the field of tyrosine phosphorylation inhibitors (tyrphostins/TKIs). He was the first to design, synthesize and prove their efficacy in cells and in animal tumor models. His work led to the development of Gleevec, as Novartis’ CEO cites in “The Cancer Magic Bullet” (2003). Levitzki was the first to show that TKIs sensitize tumors to pro-apoptotic agents. He pioneered the Trojan horse approach to eradicate tumors overexpressing

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  • Cited by (0)

    Levitzki has pioneered signal transduction therapy, especially in the field of tyrosine phosphorylation inhibitors (tyrphostins/TKIs). He was the first to design, synthesize and prove their efficacy in cells and in animal tumor models. His work led to the development of Gleevec, as Novartis’ CEO cites in “The Cancer Magic Bullet” (2003). Levitzki was the first to show that TKIs sensitize tumors to pro-apoptotic agents. He pioneered the Trojan horse approach to eradicate tumors overexpressing EGFR by targeting long chain dsRNA bound to a chemical vector guided by an EGFR ligand. This is developed as a platform for cancers overexpressing ligand induced internalizing receptors.

    Klein obtained her Ph.D. degree from MIT in 1987, and then moved to Israel for postdoctoral studies with Giora Simchen. For the past 13 years, she has been a member of the Levitzki laboratory, where her interests include basic research into understanding oncogenesis and developing targeted therapies for cancer.

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