News
Looking back on the decade in M-CM research and progress
The closing of the decade tracks closely with the life of the M-CM Network and an extraordinary story of scientific progress in a group of rare diseases.
Before the M-CM Network
M-CM was defined as M-CMTC in two papers published by geneticists in 1997. One described nine pediatric patients in England. The other paper described 13 pediatric patients in the United States.
In June 2002, parents of one of the first diagnosed patients in the UK began a website and message board to help other families find each other. This was the beginning of an international grassroots patient community that eventually migrated to Facebook.
Subsequent case reports hashed out syndrome characteristics and proposed multiple clinical diagnostic criteria. In a 2009 paper, the name M-CMTC was proposed to be changed to M-CM to more accurately describe the vascular skin involvement as capillary malformation.
Our Beginning
The M-CM Network was incorporated in September 2010 and got IRS non-profit approval in December 2010. Its reason-to-be (my daughter) was born in 2009 and turned 10 last year. The M-CM Network proceeded from the question of whether or not M-CM patients need Wilms tumor screening, and the idea that a registry could bring clarity to that question.
We also began thinking about other ways that a formal organization could complement and serve the already existing patient community. There was at the time a huge gap in information and education about the condition. With the help of an expert geneticist and genetic counselor, we were able to quickly publish a robust syndrome description that filled a gap in information available to patients and care providers.
We also hoped to provide clarity for the name of the condition, since the original name suggested an incorrect association with CMTC lesions. However a third name, MCAP, was proposed in 2012. Despite objections from the patient community, this name has gradually been adopted by genetics databases and clinicians.
Genetic Discoveries
The story really takes off with the publication of the genetic cause of M-CM: activating mutations in a gene called PIK3CA. In most of the patients studied, the mutations were mosaic, meaning the genetic change happened spontaneously after conception, resulting in a combination of affected and unaffected cells in a single individual. Activating mutations in PIK3CA are also considered significant drivers of cancer, making them well researched.
In the same month that the genetic cause of M-CM was published, the genetic cause of CLOVES syndrome was also attributed to activating mutations in PIK3CA. Subsequently, many other named conditions have been found to have the same genetic cause and the discoveries continue to this day: fibroadipose hyperplasia (2012), macrodactyly (2012), facial infiltrating lipomatosis (2014), lymphatic malformation, FAVA, Klippel-Trenaunay syndrome (2015), some cases of venous malformation (2015), CLAPO (2018), generalized lymphatic anomaly (2019), DCMO (2020), and many individual cases of overgrowth and vascular malformations.
A workshop at the NIH in 2013 attempted to bring this group of conditions under one umbrella and sort out some of the overlapping characteristics. The result of this gathering was the term PROS, PIK3CA-related overgrowth spectrum. After the meeting, the number of conditions continued to grow.
Genetic Testing
After the gene discovery, there was still no way for most doctors to order a test for a mosaic PIK3CA mutation, so the only people that had been tested were those that had participated in research. Most of those research participants didn't have any documentation of their genetic results since they were not certified in a way that could be used for clinical care. In 2015, the first clinical test in the United States was launched.
Patients with high levels of mosaicism and germline mutations began to be diagnosed with whole exome sequencing. This has brought into the M-CM / MCAP patient population more people without the obvious characteristics of mosaicism such as body asymmetry and extensive vascular birthmarks. Many of these patients would have gone undiagnosed without a known genetic association and testing.
Testing is now widely available in both Europe and the United States, though challenges remain related to appropriate test selection and insurance coverage.
Drug Treatments
Besides aiding diagnosis, the discovery of PIK3CA as the cause of M-CM and other PROS conditions pointed to possible drug treatments. While these mutations are important in cancer, they don't show evidence of causing cancer by themselves. We benefit greatly from cancer research related to PIK3CA.
Targeting PIK3CA with drugs has been a goal of cancer researchers for a long time, but it has been a difficult target. Many drugs have been passed over by pharmaceutical companies after side effects outweighed benefits. PIK3CA is at the top of a cascade of interactions that are critical to growth and development. The early drugs were described to me as "dirty" by one researcher -- meaning they affected too much biological function and made people sick.
Drugs relevant to PIK3CA work by inhibiting the activity of enzymes that the gene produces. The enzyme produced by PIK3CA is called p110α or PI3Kα. The α stands for alpha. There are other types (isoforms) of PI3K enzymes named PI3Kβ (beta), PI3Kγ (gamma), PI3Kδ (delta). Different PI3K inhibitors affect different combinations of these enzymes. Some words used to describe these drugs are selective, meaning they target one or more specific isoforms and pan, meaning they target the whole family of PI3K isoforms.
In 2015, a paper showed that buparlisib was an effective epilepsy treatment in a mouse model of M-CM. Unfortunately, buparlisib is a pan-PI3K inhibitor and like many other PI3K inhibitors, has been abandoned in cancer trials due to its side effect profile.
Most attention to treatments across PROS conditions has happened in the vascular anomalies space where the mTOR inhibitor sirolimus has been used to treat vascular and lymphatic malformations. mTOR is the name of a gene that is lower down in a genetic pathway from PIK3CA. It is a feasible target since sirolimus is a widely used drug with an established safety profile. The use of sirolimus has not been specific to PIK3CA; it has been used for vascular malformations with varied genetic causes. Exploration of sirolimus have not had much impact on M-CM patients whose vascular malformations tend to be less focal than in the other PROS conditions.
In June 2018, a groundbreaking study was published describing the treatment of 19 patients with PROS with the PI3Kα inhibitor alpelisib. These patients all remained on the drug after two years and showed variable improvement with minimal side effects. While the study was widely publicized as affecting CLOVES patients, two of the participants had an M-CM diagnosis and are described as benefiting from the treatment. PROS patients around the world have since been able to access alpelisib via managed access requests. Clinical trials are expected this year and there is a managed access entry on clinicaltrials.gov.
Additionally, a clinical trial for an AKT inhibitor has launched for both Proteus syndrome (caused by a mutation in AKT1) and PROS. Like mTOR, AKT is further down the genetic pathway from PIK3CA. The trial design is focused on overgrowth and vascular phenotypes, but the inclusion criteria is flexible and some sites are enrolling M-CM patients.
Where are we now?
Our original objective of collecting data about Wilms tumor seems quaint now in light of all that has happened. However, data collection has uses beyond this specific question -- it's still a compelling goal. There are still many unknowns about clinical care and a new vital question has emerged: how will we measure drug benefits in the M-CM population?
There is also a challenge related to the ongoing issue of naming and defining the condition. The many many diagnoses caused by PIK3CA mutations are a conundrum for those in the business of taxonomy. Genetic testing has brought people with a greater range of effects under the umbrella of PROS. Some clinical centers are now diagnosing patients with PROS and rejecting the myriad and messy diagnostics under that umbrella. This is an improvement for those patients that would have been disconnected from a diagnosis previously, but for those whose clinical signs fit clearly within a previously named syndrome it is a loss.
The diagnostic names and boundaries will likely undergo some churn for a while longer, and patients should be included in discussions about how this plays out. The implications of diagnostic names and boundaries are different across stakeholders: patients, clinicians, researchers, pharmaceutical companies, and regulators. For patients they are important for connecting with communities of similarly affected people, a benefit that tends to be underappreciated by other stakeholders.
Here's my hopeful vision for the next decade. Pharmaceutical interest will bring new investment in research. Expert centers for clinical care will launch and patients will be able to see doctors that are familiar with and invested in their conditions. Doctors and patients will learn from each other, and patients will have a voice in setting research priorities. Doctors and researchers will collaborate across specialties to improve patient care. We will know if we should screen children for Wilms tumor. And patients will have access to all of the things that they need to live their very best lives including the most appropriate pharmaceutical treatments, surgical procedures, therapies, and assistive equipment.