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Cell Signalling Pathways: Market
for Novel Cancer Therapies
By Katherine Sheldon, Ph.D. Worldwide the market for cancer therapeutics is more than $20 billion, with annual growth rates of 15%-20%. Cancer causes 30% of all deaths in the United States, and until recently the options for cancer patients were limited. The development of new, targeted therapies is prolonging the life of cancer patients and increasing the growth of the market for oncology drugs. One reason for the increased growth is that the new selective therapies offer disease relief without debilitating side effects. Therefore, from the patient's point of view, even though they may suffer a relapse and eventually succumb to their disease, the treatment offers months or years of high quality life. Additionally, since patients live longer, the treatable population grows, increasing the market for each drug. The key to market success is efficacy without side effects, and as the understanding of the mechanisms behind cancer progression increases, new highly selective drugs are reaching clinical trials. The results of these tests will determine the blockbuster therapies of the next decade. Cell Cycle Control Advances in molecular techniques have provided a detailed picture of the mechanisms by which mammalian cells grow and divide. This process is tightly controlled in health, and aberrant regulation results in diseases such as cancer that are characterized by a lack of differentiation and uncontrolled growth. During progression through the phases of the cell cycle: G1, S (DNA synthesis), G2, and M (mitosis), DNA is duplicated and the chromosome sets are distributed evenly between the two daughter cells. To maintain the integrity of cell-cycle progression, cells proceed through several pauses, or "checkpoints." At one checkpoint, late in G1, the cell either exits to G0 and enters a quiescent phase, or commits to DNA synthesis and the rest of the cycle. A second checkpoint at G2 enables the cell to repair DNA damage before entering mitosis and creating new cells with faulty genetic information. Cell cycle progression is regulated by a family of serine/threonine kinases, the cyclin-dependent kinases (CDK), which are in turn regulated by activating cyclins and cyclin-dependent kinase inhibitors (CKI). During G1, CDKs phosphorylate and inactivate the retinoblastoma (Rb) protein causing the release of transcription factors and the induction of genes necessary for entry into S-phase. Nine CDKs and at least 15 activating cyclins have been identified thus far. The cyclin/CDK complex is short-lived, and its activity is controlled to a large degree by the ubiquitin-mediated degradation of cyclins. Additional regulation is achieved through the activity of endogenous CKIs. In human cancer, the Rb pathway is frequently non-functional. Although few tumors contain a mutation of the Rb gene itself, the common loss of function is due to hyperactivation of CDKs through an increase in CDKs or cyclins, or loss of inhibitors. Oncogenic alterations of cyclins, CDKs, and CKIs have been reported in more than 90% of all human cancers, and therefore CDKs are attractive targets for cancer therapy. Several inhibitors of CDK activity have reached clinical trials, with mixed success. Exhibit 1 Cyclins, CDKs, and CKIs in Human Cancers
Source: D&MD Publications. Protein tyrosine kinases (TK) are an integral part of the cell regulatory mechanism, acting to promote the transition of cells through G1 and past restriction points. Overexpression, amplification, or constitutive activation of TKs has long been associated with inappropriate cell cycling and neoplastic transformation. The response of tumors to cell cycle modulators varies from cytostasis to death, depending on the impact of cell cycle arrest on downstream functions. While cytostasis may not at face value appear to be a desirable response to treatment, sustained cytostasis has been shown to proceed towards apoptosis and may have the advantage of significantly reduced toxicity. Manipulation of the Cell Cycle to Enhance the Therapeutic Window Many potential therapeutics are designed to target growth factor activated pathways, however, this strategy is hampered by the fact than many tumor cells can enter the cell cycle in the absence of normal mitogenic signals. Even if the transforming event was originally due to the constitutive activation of a growth factor receptor such as a TK, the loss of suppressor genes and the over-expression of cyclins can serve to render the cells insensitive to cell cycle inhibitors. Clinically, this leads to the development of resistance to compounds that were initially thought to be highly selective and specific. An alternate therapeutic strategy is to exploit the sensitivity of transformed cells to apoptosis. Under conditions where normal cells enter a stage of growth arrest, neoplastic cells, due largely to the aberrant signals responsible for the transformation in the first place, progress through cytostasis and undergo apoptosis. Because the loss of cell cycle checkpoints is an extremely common alteration in human cancer, it is conceivable that an enhanced therapeutic window for cancer agents could be developed through the application of cell cycle inhibitors that would serve to protect normal cells by inducing G1 or G2 arrest, rendering the cells insensitive to chemotherapy. Cancer cells, which, by virtue of their transformation, lack these checkpoints would be unaffected by the cell cycle inhibitors and remain sensitive to the effects of chemotherapy. These and other innovative approaches to cancer therapy will facilitate the development and utility of highly selective agents that enable complete ablation of malignant cells while leaving normal cells unaffected. Mechanism-Based Protection of Normal Cells Growth Factor Activated Pathways. Many types of tumor cells acquire the ability to enter the cell cycle in the absence of mitogenic stimuli. This fact has been exploited in the development of drugs that target over-expressed tyrosine kinases such as the epidermal growth factor receptor (EGFR) (Iressa®), Bcr-abl (Gleevec®), and ErbB2 (Herceptin®). These drugs are designed to target the cause of the malignant transformation, the aberrant receptor, and by blocking signalling cause selective death of the cancer cells. An alternate approach, again exploiting the ability of normal cells to enter cell cycle arrest, would be to use low concentrations of growth factor inhibitors. These compounds would be expected to inhibit the growth factor-dependent growth of normal cells, while transformed cells that possess the ability to proliferate in the absence of mitogen would continue to divide and thus be susceptible to chemotherapeutic agents. CDK Inhibitors. The endogenous CDK inhibitors p16 and p21 can prevent drug-induced apoptosis by arresting growth. Experimental models have shown that over-expression of p16 or p21 causes reversible growth arrests and resistance to methotrexate, cisplatin, and paclitaxel. Loss or inactivation of p16 is a common characteristic of cancers, and therefore induction of p16 may serve as an additional strategy for inducing protective arrest in normal cells and facilitating the chemotherapeutic ablation of transformed cells. Source: D&MD To view and purchase D&MD reports click here! |
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