Yesterday Harold Varmus, Nobel laureate and president of the Memorial Sloan-Kettering Cancer Center, visited WashU and gave a talk on the “New Age of Cancer Research.” The auditorium was packed with just about every key researcher I know on campus. Tim Ley, longtime collaborator and co-director of the Genome Center, made the introduction. Together with Michael J. Bishop, Harold Varmus demonstrated the cellular origins of oncogenes – genes that control cell growth and proliferation that, when mutated, often lead to cancer – for which they won the Nobel Prize in 1989.
Dr. Varmus began with an overview of the three classes of genes involved in oncogenesis:
- Proto-oncogenes
- Tumor suppressor genes
- Genes coverning DNA integrity
The protein products of these genes have diverse biochemical and physiological functions, including enzymes (e.g. tyrosine kinases). The discovery of oncogenes led to some new paradigms of cancer research, like the design of antibodies against oncogenic proteins (e.g. Herceptin), risk assessment by inherited mutation analysis, and occasional gene expression/ mutational profiling for diagnosis/prognosis/Rx.
Improved Mouse Models of Human Cancers
Recent improvements in mouse models of human disease, specifically models in which oncogenes can be switched on or off, were the central experimental focus of the talk. Basically, his group creates transgenic mice that express, or do not express, certain genes based on whether they are fed, or not fed, doxycycline. It offers a powerful model to study short and long-term effects of both oncogenes and cancer drugs.
Tumor Maintenance Genes and “Oncogene Addiction”
One important point Dr. Varmus made is that oncogenes not only initiate the oncogenic state, they maintain it as well. Without continued oncogene expression, cancerous cells die. Mouse models of this oncogene dependence phenomenon have led to the implication of several tumor maintenance genes, including:
- C-MYC in T-cell myeloid leukemia
- H-RAS in melanomas
- BCR-ABL in B cell tumors
- MET in hepatomas
- C-MYC, NEV, and WNT-1 in mammary tumors
- K-RAS in lung adenocarcinomas
It turns out that many cancer drugs work by targeting these genes. The poster child of such designer drugs is Gleevec, which treats chronic myeloid leukemia (CML). CML is the most common form of adult leukemia, and almost always arises from the “Philadelphia Chromosome”, a somatic translocation of chromosomes 9 and 22 that creates a fusion protein, BCR-ABL. Gleevec is remarkably effective at treating human cancers; some patients are disease-free for up to 7 years.
Tyrosine Kinase Inhibitors and Lung Adenocarcinoma
Other tyrosine kinase inhibitors have proven to be potent anti-cancer agents. Dr. Varmus told the well-known story of Iressa and Tarceva (gefitinib and erlotinib), which target mutant epidermal growth factor receptor (EGFR) proteins in lung adenocarinoma. The before-after slides of the lungs of a patient treated with these drugs are quite dramatic – about 4 days into treatment, the tumors are just gone. Before treatment, she was in a wheelchair and on oxygen because of the tumor load. Two weeks later she walks into the doctor’s office on her own feet, no oxygen.
Drug Resistance
Unfortunately, there’s a sad part to the story, as is often the case with cancer. Gleevec might buy you a few years. Gefitinib/Erlotinib work are effective for about one year. After that, the tumors become drug resistant, almost always because of secondary mutations in the tyrosine kinase domain. Sometimes, other drugs can treat the resistant tumors, but not always.
Katerina Politi, a talented postdoc in the Varmus lab, developed a mouse model of drug resistance to gefitinib/erlotinib by constitutively expressing mutant EGFR but intermittently treating mice with the drugs (4 week intervals). In the drugs-on phase, most tumor cells are eliminated, but the few that survive grow in the drugs-off phase. It’s a rapid model of selection for drug-resistant tumors. This mouse model led to several revelations about the secondary mutations underlying drug resistance [see Politi et al 2006]. Almost all are in the tyrosine kinase domain of the targeted protein, but other pathways (such as MET amplification) can lead to drug resistance as well. One particular mutation, T790M, is really bad news – tumors bearing it are refractory to virtually all drug alternatives.
The Future of Oncogenic Research
Dr. Varmus left us with a few points about where cancer research should go from here.
- Genomics (and Epigenomics) – moving beyond the candidate gene approach to get the full repertoire of somatic changes in cancer. Obviously, the WashU GC is working on this.
- Progression and metastasis – there’s more to learn about how tumor cells interact with their micro-environment.
- New targets, new drugs, and better understanding of resistance – always more to learn.
- Relate cancer to development – studying the vulnerability of certain cells to certain cancer types, and working with “cancer stem cells.”
- Extend the mouse models – this guy loves a good mouse model
- Form multidisciplinary teams – bringing together people with different expertise who can all tackle the cancer problem, like the TCGA project. Also, train scientists who work both in the lab and in the clinic to gain a more complete understanding of the disease.
As Tim Ley said, it’s good to see a Nobel laureate not “resting on his laurels.”