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Archive for October, 2017

Two New Manuscripts: A Chaos Biomarker and Tracking Tumor Evolution with Liquid Biopsy

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3 October 2017

Dear Friends,

I have some good news to share. My team has had not one, but two scientific manuscripts recently accepted and published.

Part One:
Chaos *is* the Biomarker

This study was one a long time coming, that was originally selected as an oral abstract at ASCO GU early last year!

If you didn’t already know, I’m a huge fan of Siddhartha Mukherjee and his style of communication of various aspects of cancer’s biological underpinnings and history. In this Pulitzer prize-winning work (1), Mukherjee describes perhaps the most fearsome quality of what has been dubbed the “Emperor of All Maladies”

“This mirthless, relentless cycle of mutation, selection, and overgrowth generates cells that are more and more adapted to survival and growth. In some cases, the mutations speed up the acquisition of other mutations. This genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.”

This “perfect madness” described by Mukherjee exerts its effects to different degrees in different patients. It has become clear that in some patient cancers, every cell has about the same alterations that make them tick, and in some patients there is a great deal of heterogeneity in terms of what drives the disease from cell to cell (2, 3). This general movement in cancer research to acknowledge this phenomenon is happening in front of the backdrop of the “precision medicine” movement in oncology: the preferential use of very narrowly targeted therapeutics to specific alterations (4). The problem is, if one were to use a “precision” medicine with a patient with heterogeneous disease, one might eliminate a part of the disease while leaving the rest relatively intact. The patient would get all of the side effects but a portion of the benefit.

The current means to assess this phenomenon is by taking multiple biopsies in patients; cutting out multiple pieces of tissue and dissecting them to assess spatial heterogeneity of intra-patient disease. In metastatic prostate cancer, this would involve drilling into the bone in multiple locations, which is undesirable, impractical, immensely painful, and very expensive (5, 6).

We sought to determine if we could observe the echoes of this phenomenon through the circulating tumor cells in patient blood. We developed two metrics to quantify the phenotypic heterogeneity of rare cells: how different they looked from cell to cell (7).

We have been collaborating very closely with the fantastic folks at Memorial Sloan-Kettering Cancer Center, lead by Dr. Howard Scher. This collaboration allowed us to correlate patient outcome (i.e. how long they lived) on either precision therapies (abiraterone and enzalutamide), or chemotherapy (taxanes). Taxanes are microtubule stabilizers, affecting all quickly dividing cells, regardless of their drivers, including healthy cells that divide quickly. The hormonal therapies exert their influence through a very narrow molecular bottleneck (8, 9), which has less side effects and can work well, if the disease is not too heterogeneous and all of the cancer cells can be affected.

We developed two means to measure the phenotypic heterogeneity of circulating tumor cells (how similar or dissimilar cells looked to each other in a patient sample). We found that the more dissimilar they looked, the more generally aggressive the disease, and the more patients had better overall survival if given chemotherapy instead of hormonal therapy. The results suggest that the phenotypic heterogeneity of circulating tumor cells might be used to extend patient lives with more intelligent use of already existing drugs that are FDA-approved and reimbursed. A validation study is being planned. Open access article here: http://cancerres.aacrjournals.org/content/early/2017/08/16/0008-5472.CAN-17-1353

The clinical decision to give targeted therapy or chemotherapy is not unique to prostate cancer; while it remains to be tested, it is plausible that the described phenomenon and methods of measuring it could potentially be applied to lung cancer, pancreatic cancer, colorectal cancer, head and neck cancer, melanoma, and breast cancer.


Part Two: Emergent Resistance in Breast Cancer

The second study is our first study on breast cancer circulating tumor cells, and was accepted to PLoS One. Open access article here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185231

We were able to confirm the presence of androgen (male hormone) receptors on circulating tumor cells in women with estrogen-driven disease. This admittedly might sound a little odd that there are male hormone receptors present on what is predominantly an estrogen-driven disease. However, emerging models of tumor evolution suggest that women with estrogen-driven disease, for which anti-estrogen drugs are administered, can use this mechanism as a bit of a short cut back to continued cell growth: the cancer changes over time by classic natural selection and Darwinian evolution.

We were able to observe this effect in breast cancer circulating tumor cells in actual patients (10). The next step would be to determine if women with this emerging mechanism of resistance to anti-estrogens might be put on anti-androgens to control their disease, or perhaps onto non-hormone targeting therapy.

The Big Picture

There is so much that is known about how cancer starts and grows, and much about how it acts once it spreads (metastasizes) within patients, but there is a relative lack of knowledge about the seeds in transit, the liquid phase of disease. It remains a fascination of mine to do research in this space, especially since the information we glean can be turned into very clinically-friendly diagnostic modalities for better cancer management.

Thanks for dropping by!
Ryon

References

1. Mukherjee S. The emperor of all maladies : a biography of cancer. New York: Scribner; 2010.
2. Hiley C, de Bruin EC, McGranahan N, Swanton C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 2014;15(8):453.
3. Jamal-Hanjani M, Quezada SA, Larkin J, Swanton C. Translational implications of tumor heterogeneity. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(6):1258-66.
4. Shrager J, Tenenbaum JM. Rapid learning for precision oncology. Nature reviews Clinical oncology. 2014;11(2):109-18.
5. Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO molecular medicine. 2015;7(1):1-11.
6. Yap TA, Lorente D, Omlin A, Olmos D, de Bono JS. Circulating tumor cells: a multifunctional biomarker. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(10):2553-68.
7. Scher HI, Graf RP, Schreiber N, McLaughlin B, Jendrisak A, Wang Y, et al. Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer. Cancer research. 2017.
8. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England journal of medicine. 2012;367(13):1187-97.
9. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine. 2011;364(21):1995-2005.
10. Fujii T, Reuben JM, Huo L, Espinosa Fernandez JR, Gong Y, Krupa R, et al. Androgen receptor expression on circulating tumor cells in metastatic breast cancer. 2017;12(9):e0185231.

Written by Ryon

October 3rd, 2017 at 5:37 pm

Posted in Science Blog