Last week, after one year and about 4 months of work, I consented my first patient for my clinical trial of combination axitinib and pembrolizumab for alveolar soft part sarcoma (ASPS) and other soft tissue sarcomas.  Since this trial hit clinical trials.gov, I’ve had more patients come out of the woodwork with ASPS then I could have imagined, leaving me to wonder whether we’ll have any space for the “other soft tissue sarcomas” on this trial.  I’ve wanted to write this post for a long time about ASPS, the one that changed my entire career and lit a proverbial fire, so to speak.  So, without further ado… my top ten reasons why I hate alveolar soft part sarcoma…and why of all the sarcomas, which are all horrible, this one REALLY needs to get beaten.

Number 1 – ASPS is rare… really rare.  If you’ve been following my other blog posts, you know that all sarcomas are rare, making up less than 1% of all adult cancers, and 15% of pediatric cancers.  ASPS makes up only 1% of the 9000 or so soft tissue sarcomas that occur each year in the United States- or roughly 100 new cases per year.  It’s a very vascular tumor, meaning that it seems to resemble abnormal blood vessels, and a classic physical finding in these masses is the presence of a pulse or thrill, as the blood flows churns through.

Number 2 – ASPS affects kids and young adults.  The peak incidence occurs between the ages of 15-35 years old, with 60% of patients being female.  However, about 25% of cases occur in kids under the age of 18.

Number 3 – ASPS cells have the ability to spread very early.  Like most sarcomas, the majority of patients will present with a mass anywhere in the body.  In young kids, locations in the head and neck are common.  Later, most patients will have the primary in an arm or a leg.  About 60% of patients will have evidence of tumor implants outside the main tumor at diagnosis… and 40% will already have distant spread to the lungs, bones, brain, or other organs.  As of 2016, there is no cure for ASPS when it is metastatic.  If there are only a few sites of disease that can be removed, people can do better- but historically, without effective treatments, most patients will ultimately die from the disease.

Number 4 – ASPS tumors grow very slowly and are painless.  Meaning, patients often have had a mass for a long time without noticing.  Unlike other sarcomas where the rate of spread increases based on a large size and high grade (which means they tend to grow fast), ASPS spreads early when the tumors are small, and growing slowly.

Number 5- ASPS tumors can recur YEARS later.  Even with those patients who do not have spread at diagnosis, there are reports of tumors coming back or recurring in different locations as long as 20 years later.  That makes me very angry.

Number 6 – ASPS does not respond to chemotherapy like other sarcomas do…I mean…a tumor shrinkage rate of 0%.  Traditional chemo is so ineffective at these tumors, that it shouldn’t even be tried.  Wasted side effects and wasted time.

Number 7 – ASPS tumor cells are really, really hard to grow and study in the laboratory.  On top of the fact that rare diseases are not very appealing to researchers to study, because the NIH and other funding agencies are more likely to give out money to doctors studying common cancers, it’s very difficult to generate the tools to test new drugs in the lab – like cell lines in petri plates, or ASPS tumors that grow in mice.  There are only 2 or 3 cell lines in existence where the ASPS cells have been able to grow in culture.  And only recently has someone been able to induce an ASPS-like cancer in a mouse – Dr. Kevin Jones in Utah.  Drug companies aren’t excited to test new drugs in rare diseases either, because even if they work, the number of patients that will ultimately be treated is low, meaning low paychecks to compensate for doing the expensive research.

Number 8 – People haven’t heard of sarcoma, let alone ASPS… unless you know someone who has it.  Awareness is lacking for these rare diseases, and there are very few doctors who are familiar with its strange behavior and have the ability to think out-of-the-box to come up with treatment approaches.

Number 9 – Insurance companies only like to pay for drugs that are FDA-approved…making out-of-the-box treatment ideas very unappealing to them.  There are no FDA approved treatments for ASPS.  With some effort, based on small studies that have been published, there is really one drug that you can usually talk most (NOT ALL) insurance companies into covering – sunitinib.  After that… good luck.  This means that patients and doctors really need to look for clinical trials to take advantage of drugs that might be effective for slowing their disease.  That’s assuming that there’s a clinical trial available for ASPS – trials are expensive, and again, drug companies may not be interested in funding trials or even providing expensive drugs for a disease that only affects 100 patients a year.  And that’s if someone has come up with a treatment idea to even try, that is supported by some kind of research in a lab – that we’ve already discussed is not being done.

Number 10 – Where are the clinical trials?  Trials take a long time to enroll patients when there are not many patients who qualify.  And for ASPS patients, there are a lot of reasons why they may not qualify.  Common rules for participation in trials include disease that is rapidly progressing (not typical of ASPS), lack of any brain mets (also common in ASPS), measurable disease on a CT scan greater than 1 cm in size (many early patients with ASPS may have tiny, innumerable lesions in the lungs or purely bone disease which by definition is rarely measurable), age over 18…  Most trials are also not specifically for ASPS, meaning that the spots are often taken very quickly by patients with other types of sarcomas or even other cancers.  Some patients don’t have the resources to travel for a study that is being held in one center in the country – and there simply isn’t the volume of patients to make it available in enough locations to meet everyone’s needs.  In summary, running clinical trials for rare diseases, particularly ASPS, is problematic.

And now that you’re thoroughly depressed… my top ten reasons why I think that ASPS CAN be beat.

Number 1 – Even though ASPS grows slowly and spreads early, patients can live with advanced ASPS for a very long time compared to other sarcomas.  This means that usually we have some time to work to try new treatments.  I have patients with an incredible amount of tumor burden, and that much disease in other types of sarcoma would land them in a hospital very quickly.  Somehow, the body adapts and can compensate for a very long time, probably because it didn’t get there overnight.  Young patients are especially resilient and strong, too – and willing to fight.  The longer we can stall it, the closer we get to new treatments that may work better than what we have so far.

Number 2 – ASPS is genetically consistent.  Many sarcomas have a genetic code that looks like a bomb went off – a ton of broken genes that can vary tremendously from patient to patient.  ASPS is a translocation-associated sarcoma – meaning, two genes are accidentally flip-flopped during the division of a cell for unknown reasons – and they produce an abnormal protein called a transcription factor that can independently lead to all kinds of bad behavior downstream. The linkage occurs between chromosome X (again, probably the reason that this tends to happen in women) and chromosome 17, leading to a protein that’s called ASPL-TFE3.   TFE3 is the engine behind the protein, and with the abnormal and constant stimulus provided by ASPL the protein activates or inactivates several important pathways that lead to the tumor cell growth, metastasis, and other bizarre behaviors.  These pathways include:  1. Vascular proteins that stimulate blood vessel growth like VEGF and HIF-1a and their cousins, and 2. MET, a protein that is important for cell growth.  The big advance in the past ten years was recognizing the importance of tumor blood vessel factors – and led to treatments with cediranib and sunitinib, VEGF-blocking drugs.  These were the first agents that showed that the growth of ASPS could be stabilized or shrunk in some patients.   A drug called ARQ-197 is a c-met inhibitor, which also has shown some positive effects on ASPS – I have a patient who has been stable on this drug for over 6 years.  Other pathways hit by ASPL-TFE3 are similar to those found in melanoma, a cancer with a strong dependency on the immune system.  While there is still much that we don’t understand about how this protein operates, at least these cancers tend to have a common miswiring and downstream effects.

Number 3 – The immune system has an important role in ASPS.  I personally believe that the only hope of really curing any cancer is to figure out how to unleash the immune system, expose the tumor’s weaknesses, and let it do its thing.  There is no chemotherapy or targeted therapy that is a match for the cancer cell’s ability to mutate, evolve, and hide.  Obviously, given that chemo doesn’t work for ASPS, that’s even more true for this disease.  The best medicines we have, the VEGF blockers like cediranib and sunitinib, can hold it steady for a period of time, but no cures that I’m aware of from these drugs so far, and most patients ultimately develop resistance.

However, the immune system has the ability to learn, recognize, adapt, and remember.  As I’ve waxed poetic in other posts, the immune system has the versatility to take on cancer… but it needs time to work, and we need to make sure that the cancer’s camouflage is lifted and the rapid growth and spread is halted long enough for the immune system to catch up and get it done.  There are stories in ASPS of patients who had metastatic disease, and when all of visible disease is removed, somehow the residual tiny tumors begin to melt away.  There are also those patients who have localized disease, and even though we know that ASPS leaks cells into the circulation very early, they just don’t ever grow new tumors.  To me, that screams loudly that the immune system has to be doing something already in this disease.  The problem is that for most patients, by the time the disease is advanced, it’s just not strong enough on its own to catch it.  So… we have to figure out how to make the immune system work better.

Number 4 – ASPS depends on an unusual type of metabolism for its energy and growth.  Our normal cells have evolved a highly efficient process to generate energy, however many cancer cells have abandoned this and grow using a backup pathway called glycolysis.  Glycolysis is inefficient, and creates large amounts of a waste product called lactic acid.  When you’re working out, your muscle cells start out using the efficient pathway, but if you keep pushing them past the limit, they have to switch to the glycolysis pathway, building up lots of lactic acid. The accumulation of that material leads to muscle soreness the next day.

ASPS not only uses this process, but it THRIVES on lactate.  Dr. Jones has showed that the cells not only use it as fuel, but the high lactate actually shifts around other pathways in the cell that help it adjust to living in a low oxygen environment and promote the formation of those bad tumor blood vessels that are classic for the disease.  This tendency actually opens up other ideas for therapeutic treatments – if you could give glycolysis-blocking drugs, you may be able to cripple the growth of these tumors, while largely sparing normal cells which use the more efficient pathway.  Many of these drugs are being investigated in other types of cancer as well.

Number 5 – ASPS, like other translocation-associated sarcomas, seems to rely on epigenetic changes to facilitate its bad behavior.  So in other discussions of cancer, people talk about key genes being mutated, or broken – there’s a mistake in the code that changes the way the proteins function and that broken protein drives growth and metastasis.  Sometimes, it’s not that the gene is broken, but that it is abnormally switched on, or switched off.  All of our cells have all of the same genes physically located in the hub of the cell, or the nucleus.  But for example, a cell whose job it is to make digestive enzymes in your stomach doesn’t need to same proteins that a cell in the kidney needs to regulate the flow of salt and water through urine.  Epigenetics is a system that GLOBALLY regulates which genes are switched on and which genes are switched off in cells.  Most cancers have a high degree of “switched off” relative to normal cells, and there are particular enzymes (HDAC for example) whose job it is to place shut-off tags on the start buttons of genes and turn them off.  We have drugs that will block these enzymes, decreasing the suppressive tags across all of the genes, allowing cancer cells to slowly return to a more normal “on” state.  These drugs tend to work slowly, and in complex cancers with a lot going on, like most “solid” tumors, it hasn’t been a miracle in and of itself.  But sometimes treating with these drugs has shown to lead to better responses to treatments that come afterwards – like the cancer cells were reprogrammed.  This is an area that needs more investigation in sarcomas, but early studies suggest that in “simple” translocation sarcomas like ASPS, there’s plenty of HDAC around, and that epigenetics are an important target.

Number 6 – We have drugs for the major potential targets identified so far in ASPS.  As I’ve explained so far, everything we have identified points to really a few key chinks in the armor of ASPS – they rely on vascular growth proteins like VEGF, c-MET (a protein that also stimulates tumor blood vessel development), abnormal metabolism, a blinded immune system, and faulty epigenetics.  We have drugs that can act on all of these things, identified in efforts to treat other cancers.  One of the hallmarks of cancer is that when you try to block one target only, ultimately the cancer cell figures out how to work around it.  Thus, one thought is whether we should be hitting these tumors with combination treatments.  Some of this has been tried in other cancers – and combinations now are a huge focus with checkpoint inhibitor immunotherapy drugs, including with anti-VEGF drugs as well as epigenetic drugs.  The problem with combinations is that you can ultimately get severe side effects when you’re blocking multiple pathways at one time, even though the normal cells don’t rely on the proteins that much by themselves – so this remains a challenge.  We have the tools – but how can we use them more effectively together?

Number 7 – We are learning how to do clinical trials in rare diseases like ASPS.  The National Institute of Health runs an ASPS clinic.  Backed by government funding and organizations like CTEP, which negotiates with pharmaceutical companies to get access to drugs for clinical trials, this institute is set up to provide the much needed financial support to get patients from all over the country to its trials.  New biostatistical techniques are being developed so that conclusive results can be calculated from trials that enroll a low number of patients, allowing drugs to be tested more quickly and more cheaply.  Finally, the FDA is finally coming around to understanding that approvals for drugs that look effective need to happen without enrolling hundreds of patients in a giant, multimillion dollar phase III placebo-controlled clinical trial, especially for rare, or orphan diseases.

Number 8 – Although there are not very many doctors and researchers studying ASPS, the ones that do care, REALLY care.  We’re in the process of planning the first ASPS Research Workshop and Patient Day of Learning to be held later this fall in Miami.  Every email that I’ve sent to a researcher even peripherally involved with ASPS immediately responded with genuine interest and excitement.  That means that a substantial bunch of very smart people who are interested in ASPS and finding new treatments will be in one room, at one time, brainstorming.  Good things are bound to happen.  New collaborations, sharing of resources, pooling of ideas, and maybe, a eureka moment in the making?  ASPS is one of the featured cancers at next year’s Connective Tissue Oncology Society Meeting – that didn’t happen by accident.

Number 9 – ASPS patients and their families are a motivated bunch that are finding each other and raising their voices on social media.  The reason my trial came to be was that my first patient with ASPS and his family wouldn’t accept that there was no cure for ASPS.  They asked me to do something about it.  They started a foundation.  They helped fund research through fundraisers and awareness.  The pharmaceutical companies listened to our ideas and they got it.  We have a trial.  I still have to stop and shake my head when I think about how that actually happened.

Number 10 – ASPS IS rare.  As paradoxical as it seems, based on everything I’ve told you we are a setup for success compared to more common cancers, even the more common sarcomas.  With only a few people studying ASPS, and no one having enough resources on their own to beat this disease, we should be able to work together in collaboration rather than competition.  Without standard treatments, most community oncologists are referring patients to specialty centers, rather than trying to treat them in house.  With increasing awareness on the internet platforms from foundations, patients will become educated about the importance of seeking out clinical trials and experts in their disease, and will start to demand something better than historical statistics.   If we all work together, clinicians, scientists, and patients, I truly believe that within 5 years we can change the course of this disease, and start making up for the young lives already stolen by ASPS.