Even when non-malignant, most patients diagnosed with neurocutaneous melanocytosis—
a rare non-inherited condition of the central nervous system—face a poor prognosis if symptomatic. Although chemotherapy has been tried in some patients, it has not been effective and few other treatment options exist.
That may soon be changing though with research from Dipanjan Basu, PhD, who is testing non-melanoma drugs, like the investigational therapy omipalisib (GSK2126458) in cultured patient cells. While at the 2018 National Organization of Rare Diseases’ Rare Diseases & Orphan Products Breakthrough Summit (NORD Summit)
held in Washington, DC, Basu sat down with Rare Disease Report
®) to discuss his innovative research.
Interview transcript is modified slightly for readability:
RDR®: What did you and your team do in your study?
: “I worked with Miguel Reyes-Mugica, MD, who has a long-term interest in this disease. Being a pathologist, he developed a tissue repository for the donation of tissues for research, and also work closely with Nevus Outreach, a patient advocacy group that spreads awareness about tissue donation fundraising.
For our study, we received patient tissues and tried to tease out cells from them and grown them in the culture. We tried to find the right conditions that favored the growth of those and maintain them in the lab so we could use them as a model to test drugs.
We tested a few of the non-melanoma and melanoma drugs targeting the specific genetic mutation in these cellsvand recorded the results of how many days it took a drug to kill the cells. We thought it would be beneficial if we specifically targeted tumor stem cells carrying the genetic mutation.
Our main contribution with this study is to be able to grow and maintain these cells as colonies, which isolate the tumor stem cells from the others in the culture.
[It is important to note that] the heterogenous population has some cells that are not tumor stem cells. Some cells are tumor stem cells. We tried to grow them in a way that basically isolates the tumor stem cells in the culture. That’s the main thing that we did, and we tested drugs on that culture, and our results indicate the efficacy of the drug on tumor stem cells in this disease. We think this is a whole new approach.”
RDR®: What were the key findings?
: “There are 2 things that deviate us from the existing paradigms.
One of the findings here is that the genetic mutation in NRAS
that turns on the cellular signaling network in adult melanoma works differently in these cells. We observed some kind of redundancy in that the signaling pathway activated due to the mutation also depends on the external factors present. There is not a dedicated signaling circuit for this mutation in these cells, as was thought before. Instead, if you change the extracellular factors present, then the signaling circuitry used by the cell would be different. That’s 1 thing that we learnt in this study. Basically, if you’re not targeting the right pathway, you’re not getting the desired result.
Second, one of the drugs that showed a lot of promise was a drug that was already in the pipeline for approval for another disease called idiopathic pulmonary fibrosis (IPF) and has been well tolerated by patients.
When I started the study, the drug was being considered for a cancer clinical trial as well, so we wanted to target 2 pathways at a time using that drug because it was targeting a kinase in the signaling pathway of the mutated gene as well as another kinase, which would make it more powerful. We chose that drug and it worked very well in our hands.
That’s an advancement I would recommend physicians and clinicians to keep an eye on because it may get approved in the near future, and then they could try it out.”
RDR®: What drug is this?
: “It’s called omipalisib (GSK2126458). It is being tested for fibrosis as well as cancer. I think it was well tolerated for fibrosis but not yet for cancer, so we will have to see how it goes.”
RDR®: What do you want them to take away from your study?
: “We need to shift the paradigm from how we look at the disease because a pediatric disease is not like a smaller version of an adult disease. Children are not little adults. I am gonna quote Dr. Reyes here—"they are children.”
The manifestation and molecular nature are different, and the way we treat them should be different. The current thinking that the melanoma drugs for adults targeting the same genetic mutation in this disease as well may not be true, so we are proposing a shift in the paradigm to specifically target these undifferentiated cells with the mutations that are present in the tumor.
I think clinicians should look at how to address this challenge rather than repurposing the adult cancer drugs to treat these kids. Our research shows that there is some promise; there are some drugs that might work. In the near future, I think we should keep an eye on these drugs and find out how they can help these kids.”
RDR®: What are the next steps with your research?
: “As a young investigator, I am looking for funding all the time. Being a rare disease researcher is a challenge.
However, I plan to make a mouse model that would reflect—faithfully—the human disease so that we could do a bigger drug screen. Omipalisib came out as effective, but if it’s not well tolerated, we can get other molecules to test. Since the research will be at the organismal level, it will give us more information on the tolerability, toxicity etc, and how this molecule may work as a potential drug.
I plan to make the mouse model and look more into the molecular nature of the cells and how the tumor grows and spread as well as what other targets we can explore.”
Dr. Basu’s study, titled, “The Dual PI3K/mToR Inhibitor Omipalisib/GSK2126458 Inhibits Clonogenic Growth in Oncogenically-transformed Cells from Neurocutaneous Melanocytosis
,” was published in Cancer Genomics & Proteomics