The March 29, 2016 Wall Street Journal reported a 23-year-old man with acute myeloid leukemia (AML). Using genomic (DNA) profiling a FLT3 (FMS-like tyrosine kinase-3) mutation was identified and Sorafenib, a drug that targets FLT-3, provided benefit. When he relapsed a second treatment provided a second brief remission. At the one year point, a new mutation was identified and a third drug allowed him to undergo a second bone marrow transplant and he achieved a remission.
This gratifying story reflects our growing understanding of "driver mutations", those genetic changes that can “drive” cells to become cancerous. The first breakthrough of this type provided us Imatinib (Gleevec) for treatment of Chronic Myelogenous Leukemia (CML), another form of leukemia. Related discoveries continue to provide a growing list of agents for blood borne (hematologic) cancers.
Even in the absence of “driver mutations” successes are possible as we and our colleagues from Sao Paulo recently reported. Using the EVA/PCD™ platform we identified targeted agents for leukemia patients who had failed all known therapies including bone marrow transplants. Five of seven heavily treated, drug refractory patients responded to our drug selections, most with no known “target” gene mutation. This reflects the complexity of tumor biology and the realization that normal genes can be used abnormally by cancer cells to enhance their growth and survival.
We rejoice in these successes but are reminded that blood borne tumors represent about 10% of all cancers. It is the common solid tumors that have proven harder to target. This may reflect unique features of the hematologic tumors with their greater sensitivity to many forms of therapy, both targeted and non-targeted. Unfortunately, for patients with colon, advanced breast, recurrent ovarian, pancreatic and most lung cancers, survival has changed little in decades. To address these solid tumors, we must broaden our sights and use all available approaches.
Non-Small Cell Lung Cancer (NSCLC)
NSCLC is one of the most complex human malignancies with some patients carrying driver mutations that can be targeted with available drugs. One of my patients originally presented with a Stage IV NSCLC that responded to 1st line chemotherapy, but then relapsed. We met the patient and conducted a biopsy that identified a 2nd line chemotherapy that provided remission for a year. At the time of his 3rd relapse, we removed a metastasis from his adrenal gland that revealed an entirely new sensitivity to a targeted drug. Having eliminated the first clone of cells and then the second, we were confronted with a new population that responded immediately to a novel therapy and he remains in remission now over a decade since original NSCLC diagnosis.
There are many lessons:
Blood-borne tumors may be unique in their responses to many classes of drugs.
- Cellular biology is best defined and studied at the level of phenotype (function).
- We must use our skills to target all operative mechanisms of cancer progression.
- We must re-double our efforts to study the common lethal malignancies.
The Wall Street Journal story is indeed gratifying but there are too few of these of stories in lung, pancreatic and colon cancer. That is where additional effort needs to be focused.
As always, I welcome your questions and comments.