Cancer Metastasis: Treatment Challenges, Therapy Improvements and New Medical Devices for Targeting It
Ann Nguyen:
Hello, this is Ann Nguyen, Senior Associate Conference Producer with Cambridge Healthtech Institute. We are here for a podcast for the 2nd Annual Liquid Biopsy Summit, happening this June 21-23 in San Francisco, California. Let's welcome one of our speakers and short course instructors, Dr. Stuart S. Martin, Professor of Physiology with Greenebaum NCI Comprehensive Cancer Center at the University of Maryland School of Medicine.
Stuart, thanks so much for joining us.
Stuart Martin:
Great, Ann, it's a pleasure to participate in this podcast.
Ann Nguyen:
What are the most significant challenges encountered when treating cancer metastasis?
Stuart Martin:
Well probably the biggest challenge with treating cancer metastasis is really a problem of imaging. So I think as we all are aware, the majority of patients succumb to metastatic disease rather than the primary tumor which is generally fairly easily removed by surgery. The problem with trying to treat the metastatic disease is the threshold of detection for clinical imaging. For breast cancer, that would be MRI, PET, CT, or mammograms. By the time a tumor first appears with those clinical imaging methods, it has reached a size of more than 10 million tumor cells. So we're catching metastasis at almost too late a stage to really do anything effective about it.
And so this leads to a lot of different problems, one of which is there are very different ways that cancer cells can metastasize. One method would be single cells that lie dormant in distant tissues without really going through the cell cycle. Those dormant cells are highly resistant to traditional chemotherapies that target dividing cells. And so they're not very well detected. In fact, they're completely invisible to our current clinical imaging methods and we don't have good drugs to destroy them.
Now the problem with such poor imaging and detection methods is we also can't distinguish the difference between single cells that are sitting dormant and what I would call sort of a smoldering disease where you have small tumors of maybe less than a million cells or scattered across organs that are continuing to grow and die, but they exist below our detection threshold. And so that is really a much more dangerous phase of disease, because you're selecting for resistant mutants, you're selecting for cells that might escape the therapies, but you still can't see them, until they arrive suddenly in multiple organs and the patient unfortunately dies from that.
So that's really the challenge of both detecting metastatic disease but then that also shapes our ability to develop drugs to target those phases, because we literally can't see them in patients. And so designing a clinical trial to find an effective metastasis drugs is still something that's really hampered by our detection limit.
Ann Nguyen:
Speaking of drugs, what steps have to be taken to improve therapies to reduce cancer metastasis and what kind of progress has been made on that front?
Stuart Martin:
So this is one area where The Liquid Biopsy Summit is really focusing on some of the developments in circulating cell-free DNA and RNA as one of the more sensitive detection methods that's coming online. And so as I was just describing, the inability to detect metastatic disease makes it difficult to develop those therapies. And so some of the methods that have been done from blood samples using personalized PCR-based tests to detect a patient's tumor recurrence have shown that the ability to see the recurrent tumor coming back with circulating tumor DNA can precede the ability to detect with imaging by over a year. And so just the fact that you can start to see disseminated disease coming back will now allow you to introduce therapies and see whether they drive down the tumor burden or whether it continues to increase long before you would ever see it with imaging.
So this is leading to a whole host of new approaches. One of the most exciting is drugs like checkpoint inhibitors that are targeting the immune system response and attempting to break the tolerance that has the immune system has for the tumor by shutting off the signals that the tumor is using to suppress the immune system. So this gives the immune system a chance to now attack the tumor but combined with the sensitive detection of disseminated disease with things like ctDNA, it gives us the ability to catch the recurrence at an earlier phase and intervene and then importantly determine whether that intervention has made a difference.
And so beyond immune system therapies, that also opens the opportunity to develop drugs that would target this metastatic phase and the types of drugs that would be completely overlooked by current approaches that are focused on tumor growth rather than the ability of the tumor to survive in distant tissues and find its way to organs during metastasis.
Ann Nguyen:
You addressed drugs specifically and therapies. Let's veer a little bit to new medical devices. When it comes to bioengineering new medical devices for targeting cancer metastasis, could you elaborate on some of those promising, exciting developments over the next 5-10 years?
Stuart Martin:
I'd saw there's a real innovation phase going on right now where there are literally 30 companies or more that are focused on the capture of live CTCs and new ways of isolating circulating tumor cells from the blood samples of patients. And of course, the great attraction of this is following cancer's recurrence through blood samples is something that can be done continuously in patients during that phase where their disease is generally considered in remission but we know that it can be sort of growing and shrinking and being able to capture these live CTCs opens the possibility of analyzing them for genetic alterations or potentially even testing them for drug response.
And so that in combination with the innovations that are being done as we just talked about, circulating tumor DNAs, give the ability to really assess what would be the problem of tumor evolution. So because the metastatic tumors are growing out in a site that's different from their primary organ, the selective pressures that are placed on those disseminating tumor cells are different from the primary organ. So the mutations that are going to be selected for in the metastatic disease are often very different from those in the primary tumor. And so being able to detect those genomic changes either with circulating cell-free DNA or RNA or by capturing the live CTCs now gives you the ability to determine how has the metastatic disease changed and how should we alter patient therapy to more directly attack it?
And then beyond that, there's been some fairly significant advances in the ability to grow and expand patient tumor cells to essentially give a personalized culture for an individual patient. And so some of those approaches of course are the patient-derived xenografts that people are familiar with where the tumor is taken directly from the patient and transplanted into the matching tissue of a mouse to give a more appropriate tissue environment. The disadvantages of the PDX method is it generally takes a very long time, six months to over a year for the cells to grow in a mouse. And so there have been other developments in terms of improving in vitro culture methods for circulating tumor cells and patient tumor cells that hold the promise of essentially growing up a culture of the cells that are recurring metastatically in a patient that give you a platform to optimize existing therapies against those cells or use them as a platform to test new therapies.
And so those bioengineering approaches that capture live CTCs, the improvement of detection of circulating cell-free DNA and RNA, as well as some of the in vitro and mouse-based culture models are things that I think are really going to improve our ability to attack metastatic disease more effectively.
Ann Nguyen:
Well, sounds like the field is brimming with a lot of promising new technologies and strategies and we really appreciate you taking the time to share some of your observations and insights into this, Stuart.
Stuart Martin:
Absolutely. My pleasure, Ann.
Ann Nguyen:
That was Stuart Martin of the University of Maryland School of Medicine. He'll be speaking during Day 2’s Precision Oncology: Monitoring Therapy Response at The Liquid Biopsy Summit, which runs this June 21-23 in San Francisco.
To learn more from him, visit www.liquidbiopsysummit.com for registration info and enter the keycode “Podcast”.
This is Ann Nguyen. Thanks for listening