Many are familiar with the brilliant success of chronic myelogenous leukemia (CML) using the targeted drug known as Imatinib.
Before Imatinib bone marrow transplantation was the only curative treatment. But when investigators at the University of Oregon recognized that each cell in CML carried exactly the same gene mutation, Imatinib virtually cured the disease overnight. CML went from a killer to a cure.
This has been the subject of review, but the miracle of CML has proven very difficult to repeat, particularly in solid tumors.
Cancers Are Not All The Same
The first inkling came in non-small cell lung cancer using drugs that block epidermal growth factor (EGFR). But successes were often short-lived as drug resistance set in.
This was followed by drugs that target ALK, then ROS-1, then MET and RET but like EGFR, tumors developed resistance and over time these targeted drugs also lost effect.
Despite these incomplete successes, the experiences are instructive as they show that cancers are not all the same; that targets do exist, and that these targets can be attacked to eliminate at least some tumors. Though the CML story hasn’t been fully duplicated, the EGFR, ALK and related advances are emblematic of potentially better, smarter therapies that may lie ahead.
Might rare tumors offer the way forward? The reason for this optimism comes from the fact that not unlike CML, rare cancers often carry unique attributes that drive tumors. That one difference separates them from all other cancers.
Epithelioid Hemangioepithelioma (EHE)
One example is a rare sarcoma that afflicts young patients known as epithelioid hemangioepithelioma (EHE). EHE is associated with a very specific gene fusion known as WWTR1-CAMTA1. But, beyond surgery, there are very few effective treatments.
My interest was piqued when I received a call from a 26-year-old woman in Bahia, Brazil who asked for my assistance. She has metastatic EHE and is scheduled for surgery in the very near future. When I asked how she knew of our work, she offered an interesting explanation.
In October 2015 a colleague in Brazil sent a biopsy from a patient with metastatic EHE. We studied a variety of drugs and targeted agents but one drug stood out above all others: taxol.
Based on our recommendation, the patient received Taxol and now we come to learn that this provided remission, now seven years and counting allowing her to marry and raise a family.
While numerous EHE treatments exist, for this patient it was Taxol. Why, I wondered, did this one drug work so well in a disease known for its resistance to therapy?
To answer this and related questions, we need to go beyond drugs as pharmaceutical preparations and begin to explore their mechanisms of action. Once we delve into how and why these drugs work, we see cell response in a new light.
Like the movie The Matrix, where our perceptions reflect computer codes streaming past us on a screen, we need to learn to “read” the cancer chemotherapy matrix.
Suddenly this EHE patient becomes a unique target for a drug that arrests mitosis (the process by which cells pull apart their chromosomes during cell division). All the while the next patient might manifest an entirely different profile.
Connecting Patient Biology to Response
What we need to do is to drill down onto why the WWTR1-CAPTA1, characteristic of EHE, conferred such sensitivity to Taxol and then connect this patient’s biology to her response.
Cancer patients get better for good reasons and we should not rest until we find out what they are.
In research, the number of people in a study or trial is known as “N” and single-patient experiences are known as an “N of 1.”
These “N of 1” experiences can guide us to remarkable insights if we are ready to listen. Using our laboratory platform to interrogate tumors drug by drug, we are able to provide those insights.
Let’s make sure we are listening.