Dr. Nagourney's Blog

For Some Cancer Patients, A Bad Gene Can Be A Good Gene

By Robert A. Nagourney, MD

Ironically, many of the worst cancers prove to be the easiest to treat when new discoveries are made.

Hairy cell leukemia, once the bane of hematologists, is now cured with a single course of 2-CdA. Chronic myelogenous leukemia (CML), considered uniformly fatal without a bone marrow transplant, is now easily managed with a pill a day. Multiple myeloma and many of the most aggressive forms of lung cancer have emerged as easy targets for the newer forms of treatment.

Regrettably, these advances, however dramatic, still represent only a fraction of all cancers and there is much work yet to be done. 

One of the most challenging forms of breast cancer is the basal subtype often associated with triple negative (ER, PR, HER-2 (-)) disease.

It is aggressive, disseminates early and can be resistant to conventional chemotherapy. Although we have had good How We Test Your Cancer Infographicoutcomes in some patients using Platinum-based treatments (Blog June 2016) many patients remain difficult to manage. New insights from researchers in Florida and South Carolina offer a tantalizing opportunity to address this difficult disease.   

The Case of MYC

Among the most dangerous DNA mutations (oncogenes) in human cancer is one known as MYC. It is associated with the most aggressive form of lymphoma (Burkitt’s Lymphoma) and with childhood neuroblastoma. It now appears that it may play a role in triple negative breast cancer as well.

Working in cell culture and animal models investigators found that the presence of the MYC oncogene was associated with an improved survival. How could this bad gene possibly be a good gene for patients with triple negative breast cancer? The answer lies in MYC’s role as an orchestrator of a highly complex signal network.

Paradoxically, when MYC expression goes up in certain breast cancers, it reins in invasiveness and the ability to spread. But this only applies to triple negative cancers, not to the more common estrogen driven types. When they examined what MYC actually controls that improves patient survival, the story got even more interesting.

MYC & SRC

Using sophisticated tools to increase and decrease MYC they found a second control pathway, known as SRC.  Strikingly, if you simultaneously inhibit both pathways (MYC and SRC), you get dramatic effects in the cancer cells. But this only occurs if you target BOTH pathways at the same time. In fact, inhibiting MYC alone was actually worse. 

The problem is that there is now a fever-pitched attempt to develop drugs that control MYC. With these new findings, however, could MYC-targeted therapies prove hazardous? The answer, it would seem, is yes! It may be that in certain circumstances these well-intentioned interventions designed to target MYC could prove dead wrong. 

We recently reported our findings in this field (Nagourney et al Proc. ASCO, 2016) where we examined drugs that target MYC. Interestingly, drugs that are now used for hematologic malignancies have activity against both the MYC and SRC pathways. We are now exploring these findings in triple negative breast cancers to see if a relatively simple, oral drug combination might offer a novel therapy for some of these patients. 

This study is of interest on many levels.

  1. A bad gene may in certain circumstances be a good gene.
  2. Events in cancer are highly contextual, such that a good gene in one form of breast cancer (triple negative) may be a bad gene in another (ER+).
  3. The complexity of these associations goes beyond our ability to simply identify a gene as present or absent at a DNA (genomic) level. We must be able to gauge the biological consequences of these interwoven events. This is best done at the level of cellular biology (phenotypic).  

Each of the observations in this study ultimately required a cellular system to examine the complex interaction between genes and their inhibitors. This is precisely the work that we conduct using ex vivo analysis of programmed cell death (EVA/PCD) in human cancers. 

Most importantly, we may have a new handle on triple negative breast cancer that uses commercially available drugs that are combined in entirely new ways. We will now pursue these observations in our triple negatives. If we can confirm these interactions, it may offer an effective new therapy for our patients with this aggressive disease. 

As always, I appreciate your thoughts and comments.