Fred J. Schreiber, M.D., Hematology/Oncolog

Targeted therapy is one of the most encouraging concepts in anti-cancer treatment today, One might ask, “Hasn’t chemotherapy always been tar- geted against cancer?” That is certainly the case, but our current treatments are designed to try and interrupt abnormalities specific for the malignancy.

Leukemia offers two good examples. Promyelocytic leukemia is character- ized by disseminated intervascular coagulation, generally low peripheral blood count, and leukemic cells arrested at the promyelocytic stage. Chromosomally, this leukemia is characterized by translocation between the 15th and 17th chromosome. This results in a new genetic sequence made up of the retinoic acid receptor gene and the pml gene. This new genetic sequence results in the maturational arrest. When treated with transretinoic acid, the block on maturation is released, the leukemic cells mature to fully formed neutrophils and in a significant percentage of patients in a remission. While chemotherapy is also able to induce remissions, it is generally with the increased risk of coagulopathy. The combination of trans-retinoic acid and chemotherapy achieves even bet- ter clinical remission than chemo alone.

Chronic myelocytic leukemia also provides an example of targeted thera- py. Chronic myelocytic leukemia is characterized clinically by white cell count elevations, splenomegaly and thrombocytosis. Chromosomally, this disease is characterized by translocation between the 9th and the 22nd chromosome. This results in a unique new genetic sequence labeled bcr/abl. This unique genetic sequence results in a unique messenger RNA sequence which in turn results in a unique protein form. This pro- tein is a kinase created by the two adjacent genetic sequences. This kinase remains in a perpetual activated state driving a cascade of intracel- lular reactions which leads to the myeloid proliferation and expansion. This genetic defect appears to be the fundamental leukemic process. Through the process of protein library research, multiple inhibitors have been tried and one has been found to be able to suppress the bcr/abl kinase. STI 517 (Gleevec) is a specific inhibitor of that kinase. Therapy with it will result in decreased marrow proliferation, normalization of blood counts and in a small percentage of people, the abnormal chromo- some will disappear. Presumably, the latter represents disappearance of the leukemic cell line. The normal marrow cells not containing the altered kinase are not suppressed.

The common epithelial malignancies (lung, breast, colon, etc.) do not at this point have genetic anomalies serving as targets for therapy. In gener- al, their growth and cell/cell interaction is regulated by growth factors and the receptors located on their cell surface. To date, one of the best characterized is the epidermal growth factor and its receptor. This is a large molecule with a portion extracellular, a portion intracellular, and a connecting chain transiting the cell membrane. The intracellular portion functions as a tyrosine kinase and when active will result in a cascade of intracellular reactions leading to cell division, proliferation, etc. Many epithelial cancers are characterized in part by the increased number of growth factor receptors on their surface.

Therapies directed against the epidermal growth factor target either the extra or the intracellular portion. ZD1839 is a small molecule capable of intracellular penetration and subsequent interference with the enzyme portion of the receptor. Once suppressed, it no longer stimulates the intracellular pathways. Our current trial using this agent in refractory non small-cell lung cancer for previously treated patients now felt to be resistant to standard cytotoxic agents. Even in this markedly drug resist- ant state, it has a 10 percent response rate with modest toxicity. Similar agents have been moved to the front line therapies of non small-cell car- cinoma. Tarceva (OSI 774) is another small molecule directed against the intracellular component of the epidermal growth factor receptor. It is being combined with cytotoxic agents for previously untreated non small- cell carcinoma of the lung, stages 3 or 4.

The epidermal growth factor receptor has multiple isoforms. In breast cancer, one form is Her-2/neu which is overexpressed in roughly 30 per- cent of cases. This overexpression on the cell surface is a direct conse- quence of amplification of the gene for this epidermal growth factor receptor, presumably as a consequence of the malignant transformation. Overexpression describes a more malignant phenotype with increased risk of recurrence following surgery, shortened survival, and resistance to some chemotherapy agents. Herceptin (Trastuzumab) is a large molecule capable of binding to the extracellular portion of the epidermal growth factor receptor, and subsequently inhibiting its activity. By itself, it has a roughly 15 to 20 percent response rate for metastatic breast cancer, but when combined with chemotherapy, response rates that are better than additive have been found. This is currently in the phase 4 study at the Center for Cancer Care and Research combined with a taxane for first line treatment of metastatic disease.