Anticancer Drug Development Trends: Translational Medicine

May 2008, Vol 1, No 4
Caroline Helwick
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More than 17,000 of the world's best cancer scientists convened in April in San Diego for the annual meeting of the American Association for Cancer Research (AACR). Breakthroughs in molecular targeting of the seemingly limitless tumor-cell–signaling pathways were highlighted in many of the 6000 abstracts presented.

Eileen P. White, PhD, Chair of the AACR 2008 program committee, noted, "This meeting is...a showcase for...the best science that is happening everywhere: the best molecular biology, cell biology, drug development."

The common goal of these research efforts is to bring drugs to the pharmacy sooner, to save lives, the "bench to bedside" approach. "We now know that cancer is not just one disease but hundreds of different diseases. The challenge is to identify the characteristics of a patient's particular tumor and tailor treatment to those characteristics. Personalized medicine is critical to this process and is the aim of the future," Dr White said.

Laboratory research is moving rapidly into the clinical setting, she noted. "Basic and clinical sciences are merging, and this interface is what we call translational medicine."

New Pathways and Therapies

A remarkable increase is evident in our understanding of the genomic drivers of malignancy and the cellular pathways that are highjacked to support oncogenesis. Inhibitors of the epidermal growth factor receptor and vascular endothelial growth factor sound mundane now that the molecular lexicon contains so many new members. Researchers are rapidly expanding the range of tumor targets that are "druggable" by small-molecule and antibody-based technologies.

Control of translation—namely, genetic factors—is also important in the regulation of cell growth and proliferation. A number of translation initiation factors are overexpressed or deregulated in tumors or cause malignant transformation. Genes and gene complexes believed to be important in tumor formation have been recently targeted for cancer therapy.

You will be hearing more about these:

  • The protein p53 is a transcription factor activated by many stresses that impinge upon cells as they progress from normalcy to malignancy. Activation is good, but p53 is mutated in 50% of cancers (to facilitate growth) and inactivated in the other 50%. Regulation of p53 offers immense therapeutic opportunities.
  • Mutations in the phosphoinositide-3 kinase (PI3K) pathway occur in many solid tumors, and most cancers have elevated PI3K signaling. PI3K, therefore, has become a promising therapeutic target.
  • The mammalian target of rapamycin (mTOR) signaling pathway is a conserved serine/threonine kinase that helps integrate growth factor and environmental signals (hypoxia, nutrients) and regulate the cell cycle, hence mTOR inhibitor has become a focus of drug development.
  • The serine/threonine kinase Akt serves as a convergence point for many molecular alterations in cancer and controls cellular processes that contribute to cancer development. Akt activation confers resistance to many cancer therapies and is a poor prognostic factor.
  • The insulinlike growth factor (IGF) system is a linked network of growth factors, binding proteins, and receptors that are involved in normal growth and metabolism.
  • Inhibitors of c-MET and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), have been leading therapeutic targets. Inappropriate c-MET signaling occurs in virtually all types of solid tumors and can participate in all stages of cancer development. Biologics and small-molecule inhibitors directed against this pair are promising therapeutics.
  • Blockade of transforming growth factor-√ü (TGF-√ü) is expected to impede growth, progression, and metastatic potential of malignant disease. Increased expression and production of TGF-√ü occurs in many neoplasms and is associated with reduced survival.
  • Ras proteins play a key role in mediating signaling events involved in many cellular responses; therefore, critical elements of the Ras pathways are potential targets for therapeutic intervention.
  • Histone deacetylase (HDAC) is a family of 11 enzymes that help regulate cancer through their role in the control of gene expression. HDAC inhibitors selectively switch on tumor suppressor genes.
  • Heat shock protein 90 (HSP90) is a cellular chaperone protein required for the activation of several protein kinases. HSP90 inhibitors have been shown to have antiproliferative and antitumor activities.
  • The pathways of cell death and cell survival provide many opportunities for therapeutic targeting in cancer, such as with drugs targeting the B-cell leukemia/lymphoma 2 (Bcl-2) family and the tissue disturbance of the death ligand (TRAIL) receptors.
  • Proteins with specific functions in mitosis are the target of novel agents known as mitotic kinase and kinesin inhibitors, such as the epothilone class of agents (eg, ixabepilone).
  • Proteosomes have enzymatic activity and regulatory functions with respect to cellular protein turnover. Second-generation proteosome inhibitors are now in clinical development, following the success with bortezomib.
  • A host of pro- and antiangiogenic factors regulate an "angiogenic switch" that, when turned on, allows for blood vessel growth and tumor aggressiveness. Angiogenesis inhibitors targeting this switch are in clinical trials.

A Scientist Perspective

"Probably the most interesting pathway is the signaling cascade involving PI3K, Akt, and mTOR, with IGF at the receptor level. A number of compounds have been developed to block each of these components," said Alex A. Adjei, MD, PhD, senior vice president of clinical research and the Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park Cancer Institute, Rochester, NY.

In addition, cancer processes, such as the trafficking of proteins or regulation of gene expression, are also important. Many inhibitors of these processes are in development, such as HSP90 and HDAC inhibitors.

"The number of compounds directed at any one target or process reflects the fact that science has become egalitarian," he observed. "Gone are the days when we found one drug hitting a target and that one drug got to market 5 years later. Now, when the target is identified, you see 5 to 6 compounds come out of the gate at the same time. We are now in the position of having a lot more drugs than targets."

"As we understand the different molecular aberrations in cancer, the defects in different kinds of cells, we will be able to give different drugs to different patients. We will be thinking about these numerous molecular targeted agents the way we think about antibiotics today: some work for one infection and not the other."

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