2019 BCRP Vignette
Era of Hope Scholars – Making Breakthroughs in Preventing Metastasis
Yibin Kang, PhD; Princeton University; Cyrus Ghajar, PhD; Fred Hutchinson Cancer Research Center

GHAJAR
I am a bioengineer by training, and I did a post-doctoral fellowship in Mina Bissell’s lab at Lawrence Berkeley National Laboratory, and then upon starting my lab at Fred Hutchinson Cancer Research Center, I decided to really focus on breast cancer and strategies to prevent breast cancer metastasis.

KANG
I was trained as a molecular biologist and got a doctorate degree in genetics.  Then I moved to Memorial Sloan Kettering Cancer Center to do my post-doctoral training with Dr. Joan Massagué, and that’s where I started to work on metastasis of breast cancer.  And after that, I moved to Princeton in 2004, and I’ve been working at Princeton since then.

GHAJAR
I applied for an Era of Hope Scholar Award in 2013.  So we developed a proposal to target dormant cells one of three different ways: either by keeping them asleep, by sensitizing them to chemotherapy, or by identifying previously unknown vulnerabilities or dependencies of these cells on their tissue micro-environment, the normal cells that surround them.  And that proposal has been really responsible for a great deal of the innovations that we’ve been able to accomplish over the last few years.

I remember being asked, you know, so what are the likelihood that any of these ideas are going to work?  And I said, frankly, you know the likelihood that all three of them are going to work is probably pretty low, but the wonderful thing about this is, if only one of them works, it’s going to be incredibly transformative, and I think it’s really going to impact patient care and patient livelihood and survival after the diagnosis of breast cancer.  We already have shown that you can sensitize the cell that’s totally asleep to chemotherapy without waking it up.  So even if, and I’m not saying we are, but even if we were totally wrong about the pathways that are allowing these cells to survive in the face of chemotherapy, this concept that you can kill a sleeping cell is something that’s going to endure and hopefully will inspire other approaches to kill cells while they’re asleep instead of waiting for metastases to erupt.

But I think we are right about the pathways, and we’re learning a lot about how the cells survive in the first place, the cells leaving the breast and wandering into a distant tissue like the bone marrow and living there for 10 years is really an amazing thing that they’re able to do because cells aren't supposed to be able to do that.  So what are they doing to survive in this foreign country for such a long period of time?  I think we’re going to be able to identify that.  I’m hoping it’s going to be something unique that then we can leverage and take away from that cell to kill it while leaving the rest of the body, you know, completely alone.

KANG
The Era of Hope Scholar Award, the first grant I received, is a project we tried to use so-called Systems Biology approach to figure out why some patients are essentially cured after the initial surgery and adjuvant chemotherapy, but some of the patients will come back with recurrence.  And many of the recurrences are metastatic disease.  They are difficult to treat and eventually kill the patients.  So, why the same kind of tumor in the eyes of a pathologist look the same, but behave so differently?

My lab is focusing on trying to crunch the data that we have from patients and map a gene that is in the chromosome number 8, called Metadherin (MTDH), that was discovered in 2000—about 2007.  And we make the initial discovery finding this gene to be linked to a high-risk breast cancer—those that are likely to recur, to metastasize, and become resistant to treatments.  And then we create genetically modified mice to show that the gene is actually not essential for the survival of animals, but it’s important for the initiation and progression and metastasis of breast cancer.  So that’s almost like an ideal drug target—now it’s important for normal tissues but critical for breast cancer.  So we are moving from the discovery and validation of this important gene called MTDH to really use that information to identify a small molecular compound that will block the function of this protein.

Secondly is to create complicated genetic models in animals to mimic the situation that the patient already has metastatic breast cancer, and the question is, “Can we still cure the disease or at least slow it down dramatically with the drugs that target this gene?”  So this project is really exciting to us because this is really allowing us to translate the basic scientific discovery to a potential new drug for patients.

GHAJAR
I think the huge difference about the Breast Cancer Research Program is the involvement of patient advocates in setting the course of the program.  Because what it does is create a sense of urgency that I frankly feel is lacking in a lot of other funding agencies.  And you have a chance of getting funded because they want some real breakthroughs to happen.  They don’t just want incremental progress.  And so the risk that they’re willing to take is higher, knowing that there is a huge reward if that—if that risk pays off.

KANG
What I notice is that the program is becoming more and more focused into bringing the knowledge, basic scientific discovery into potential application to the patients.  Over the years we have accumulated a great wealth of knowledge about breast cancer, the molecular interconnections between different genes and different pathways, and now it’s actually the time to try to put those kinds of knowledge into practice.

GHAJAR
If you think about a breast cancer patient, they have surgery to remove their tumor, and then they’re treated with systemic therapy.  And then some percentage, a pretty large percentage, of those patients are going to relapse with metastases months or years down the road—even decades down the road.  So rather than just crossing our fingers and waiting and hoping that the therapies work, we think we’re going to be able to come up with therapies that selectively target dormant breast cancer cells, prevent them from ever being able to wake up, either by keeping them asleep or by removing them from the equation all together, so that metastases can't happen months, years, or decades later, and breast cancer survivors don’t have to look over their shoulders anymore.