Molecular Cell Biology Is Changing How Cancer Is Diagnosed and Treated

The identification of drivers of tumorigenesis has not only provided us with a molecular understanding of how cancer arises and progresses, but has also revolutionized the way cancers are diagnosed and treated. Each difference between cancer cells and normal cells provides a new opportunity to identify a specific drug or treatment that kills only the cancer cells, or at least stops their uncontrolled growth. Thus knowledge of the molecular cell biology of a tumor is critical information that can be exploited by researchers to develop anticancer treatments that more precisely target cancer cells.

Breast cancer provides a good example of how molecular cell biology techniques have affected treatments, both curative and palliative. Until the rise in the incidence of lung cancer, resulting from an increase in women smokers, breast cancer was the most deadly cancer for women, and it remains the second most frequent cause of women’s cancer deaths. The cause of breast cancer is unknown, but the frequency is increased if certain mutations are carried. Breast cancers are often diagnosed during routine mammogram (x-ray) examinations. Typically, a biopsy of a 1–2-cm3 tissue mass is taken to check the diagnosis and is tested with antibodies to determine whether a high level of estrogen or progesterone receptors is present. These steroid receptors are capable of stimulating tumor growth and are sometimes expressed at high levels in breast cancer cells. If either receptor is present, it is exploited in the treatment. A drug called tamoxifen, which inhibits the estrogen receptor, can be used to deprive the tumor cells of a growth-stimulating hormone. The biopsy is also tested for amplification of the proto-oncogene HER2/NEU, which, as we saw in Chapter 16, encodes human EGF receptor 2. A monoclonal antibody specific for HER2 has been a strikingly successful new treatment for the subset of breast cancers that overproduce HER2. HER2 antibody injected into the blood recognizes HER2 and causes it to be internalized, selectively killing the cancer cells without any apparent effect on normal breast (and other) cells that produce moderate amounts of HER2. Similarly, many lung cancers harbor an amplification of the EGF receptor locus. Treatment with the EGFR inhibitor erlotinib has dramatically increased the life expectancy of patients with this type of lung cancer.

Breast cancer is treated with a combination of surgery, radiation therapy, and chemotherapy. The first step is surgical resection (removal) of the tumor and examination of lymph nodes for evidence of metastatic disease, which is the major adverse prognostic factor. The subsequent treatment involves 8 weeks of chemotherapy with three different types of agents and 6 weeks of radiation. These harsh treatments are designed to kill the dividing cancer cells; however, they also cause a variety of side effects, including suppression of blood cell production, hair loss, nausea, and neuropathy. These effects can reduce the strength of the immune system, risking infection, and cause weakness due to poor oxygen supply. To help offset these effects, patients are given the growth factor G-CSF to promote the formation of neutrophils (a type of white blood cell that fights bacterial and fungal infections) and erythropoietin (Epo) to stimulate red blood cell formation. Despite all this treatment, an average-risk woman (60 years old, 2-cm3 tumor, 1 positive lymph node) has a 30–40 percent 10-year risk of succumbing to her cancer. This risk can be reduced by 10–15 percent by hormone-blocking treatment such as tamoxifen, exploiting the molecular data that show a hormone receptor present on the cancer cells. Mortality is reduced another 5–10 percent by treatment with antibodies against the HER2/NEU oncoprotein. Thus molecular biology is having a huge impact on breast cancer victim survival rates, though still far less than one would like.

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The discovery of the Philadelphia chromosome and the critical oncogene it creates, the BCR-ABL fusion, combined with the discovery of the molecular action of the ABL protein, together have led to a powerful new therapy for CML. After a painstaking search, an inhibitor of ABL kinase, named imatinib (Gleevec), was identified as a possible treatment for CML in the early 1990s. Imatinib, which binds directly to the ABL kinase active site and inhibits kinase activity, is highly lethal to CML cells while sparing normal cells (see Figure 24-19b, c). After clinical trials showing that imatinib is remarkably effective in treating CML despite some side effects, it was approved by the FDA in 2001 as the first cancer drug targeted to a signal-transducing protein unique to tumor cells. Imatinib inhibits several other tyrosine kinases that are implicated in different cancers and has been successful in trials for treating those diseases, including forms of gastrointestinal tumors, as well. There are 90 functional tyrosine kinases encoded in the human genome, so drugs related to imatinib may be useful in controlling the activities of all these proteins. One ongoing challenge is that tumor cells can evolve to be resistant to imatinib and other such drugs, necessitating the invention of alternative drugs.

To find more genetic alterations unique to a tumor that could be exploited for new therapies, researchers now use RNAi and genome editing technologies to identify genes that when inactivated cause tumor cells, but not normal cells, to die. This approach of identifying synthetic lethal interactions between different genetic alterations that on their own are not lethal was pioneered in budding yeast. With the development of genome-wide small hairpin RNA (shRNA) libraries (collections of RNAi constructs that target every gene in the human genome) and other genome-editing methodologies such as the CRISPR-Cas9 system (see Chapter 6), this approach is now also feasible in human cells. Tumor cells and normal cells are infected with pools of shRNA constructs, each of which harbors a unique sequence tag known as a “bar code.” After a period of growth, the RNA constructs can be isolated and shRNAs that were lost from the pool can be identified by sequencing of the remaining constructs. The shRNAs that were lost point to the target gene being essential for viability in the cell type from which they were lost. Those shRNA constructs that cause lethality in tumor cells but not normal cells suggest that the genes they target are essential for the survival of a tumor cell, but not a normal cell. This approach has been used, for example, to identify genes that, when inactivated, cause selective lethality in cancer cells harboring an oncogenic form of RAS, the K-ras oncogene. The proteins encoded by these genes could provide novel targets for the development of new therapeutics for tumors that harbor oncogenic forms of RAS.

The vision for the future of medicine is that modern sequencing technologies, as well as genome-wide RNA and protein analysis technologies (see Chapter 3 and 6), will allow doctors to classify a tumor and provide a comprehensive list of the oncogenic lesions that drive cancer growth. Treatment will then be tailored to the unique properties of each patient’s cancer. In many cancers, such as breast cancer and CML, we can already see this future taking shape.