Clinical Oncology–A New Era

Molecular Profiling

Transformation of normal to malignant cells is believed to be accompanied by considerable changes in gene expressions and protein activities. With the advent of microarray technology, molecular profiling has emerged as a powerful tool in characterizing different forms of cancer with respect to their diagnosis, prognosis and response to treatment. Mounting evidence has demonstrated that malignancies that are similar in microscopic morphology have diverse biologic behaviors and clinical courses, and these variations can be distinguished by their distinct expression patterns of messenger RNA or proteins. Using the expression data, oncologists can gain significant insights into the biology of a tumor, and can determine the tumor’s ability in response to specific therapeutic agents. The information provides an important ground for the design of specific strategies to effectively treat patients.

Taking breast cancer as an example, microarray analysis has revealed significant discrepancies in gene expression between normal and tumor cells, as well as between invasive and noninvasive cancer cells^[1]. Substantial differences in gene expression are also found in patients with BRCA mutations compared to those without mutations^[2], as well as in patients with medullary breast cancer compared to those with other basal breast cancers^[3]. Besides messenger RNA, the expression patterns of proteins are also valuable for disease characterization. Proteomic profiling of postoperative serum samples demonstrates distinct pictures of protein expression among patients with favorable prognosis compared to those with unfavorable prognosis^[4]. Furthermore, variations in genomic DNA, such as single nucleotide polymorphisms, are also found to be relevant in characterizing a tumor’s capacity of metastasis and progression^[5].

Although translating the findings of microarray research into the applications that are feasible and affordable in the clinic remains to be a challenge, molecular profiling not only promotes the identification of molecular signatures for diagnosis and prognosis, but also fuels the discovery of new molecular targets for treatment.

New Therapeutic Targets and Agents

Continuous emergence of new therapeutic agents is another excitement in clinical oncology. For the first time, humanized animal antibodies raised against specific molecular targets have been demonstrated to be therapeutically effective in treating cancer patients. Herceptin (Trastuzumab, Genentech) is the first of this kind that inhibits the activity of HER-2/neu receptor which belongs to the family of epidermal growth factor receptors (EGFR), a type of tyrosine kinase receptor located on cell membrane transmitting mitogenic and anti-apoptotic signals. A large number of experiments and clinical trials are currently underway to test various new drugs that can interrupt tyrosine kinase receptors, which include those suppressing the activity of insulin-like growth factor type I receptor and those blocking signal transmission of the downstream molecules, such as Akt and mTOR^[6,7].

Recently, the Food and Drug Administration in the US has approved several new anti-cancer drugs for clinical use, which include Erbitux (cetuximab, Bristol-Myers Squibb) for squamous cell carcinoma in the head and neck or advanced colorectal cancer, Nexavar (sorefanib, Bayer) for advanced renal cell carcinoma, and Sutent (sunitinib malate, Pfizer) for advanced renal cell carcinoma or gastrointestinal stromal tumors. While Erbitux is a monoclonal antibody against EGFR, the latter two are small molecules capable of blocking the activity of various receptor tyrosine kinases. Compared to the conventional chemotherapeutic agents that obstruct cell division and replication by either non-specific damage of DNA molecules or inhibition of mitosis, the new generation of anti-cancer drugs focus on targeted interruption of specific cell signal transduction pathways that are crucial for tumor cell growth, proliferation, survival, and spread. Other drugs that are under research and development include those that target tumor cell invasion and metastasis, such as the angiogenesis inhibitor Avastin (bevacizumab), an antibody against VEGF, and MMP (matrix metalloproteinase) inhibitors^[8]. Drugs focusing on epigenetic regulation of gene activity, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, are also under extensive investigation^[9].

New Treatment Strategies

Clinical use of new therapeutic agents also facilitates the development of new treatment strategies. It has been shown that combining different drugs that target different signal transduction pathways or different cellular activities can generate powerful therapeutic synergy. For example, using an anti-EGFR antibody (cetuximab) in combination with an anti-VEGFR antibody has been found to be more effective than using either single agent alone in animal models^[10]. Last year, two large randomized clinical trials demonstrated that using Herceptin in combination with standard chemotherapy in treating breast cancer could reduce recurrence by more than 50% when compared to using chemotherapy alone^[11]. Studies also suggest that using chemopreventive agents may improve the effect of cancer therapy ^[12].

Tumor Microenvironment and Systems Biology

Another new developing area in clinical oncology research is tissue microenvironment and systems biology. Tissue microenvironment has emerged as an important factor in malignancy, especially in cancer progression and metastasis. It is believed that tissue microenvironment plays critical roles in the proliferation, invasion, and metastasis of cancer cells. To fully understand the impact of the tissue microenvironment on cancer, one should consider the approach of systems biology, in which the majority, if not all, of molecular constituents in a particular tissue or cell environment are evaluated and studied simultaneously as a complete dynamic entity. Understanding the tumor microenvironment and the content of systems biology further stimulates the development of therapeutic strategies that can attack multiple targets to improve therapeutic efficacy.

With these new exciting developments in clinical oncology, the issues facing oncologists are not only how to apply these new ideas, technologies, and therapeutic drugs into their research and clinical practice, but also how to advance the field by incorporating unique Chinese components, such as traditional medicine, into it, making the application and practice more pertinent for all patients.