Meditations of an oncology geek

Impressions: 2nd annual Pedal the Cause

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29 September 2014

One week ago concluded the second annual Pedal the Cause. In lieu of a lengthy piece, I would like to present ideas / impressions that constitute small pictures of a larger portrait. And photos.

Temporary Pain
Let’s face it, riding 170 miles through mountainous territory is pretty hard regardless of the pace. There *will* be some pain and discomfort along the way. But, that’s sort of the point. Cancer patients go through tremendous pain and discomfort through the process of their disease and treatment, and a little bit of athletic-induced physical hardship is a great means to both empathize with cancer patients and to learn to appreciate our good health.


Image: at the finish line at UCSD on Day 2, 170 miles in our legs and smiles on our faces. I’m on the left.

Cameraderie
Everyone at the Athletes’ Village in Temecula made the distance. Everyone had a story about their ride, about their life, and about cancer. Pedal the Cause brings together a truly impressive caliber of people that would be worth riding 170 miles and raising thousands of dollars to be able to spend an evening in the company of.

Image: The evening in Temecula brought together cancer survivors, patients, caretakers, and well wishers. And jokes by Bob Roll. Photo:A.Czapracki

Health Promotion
Even if every research project funded by Pedal falls flat and fails to produce anything that will be of great value to cancer patients (a highly unlikely scenario), Pedal does one thing that is so essential: health promotion. There is one thing that we can never get back: time. None of us know with certainty how much time we have remaining in our lives. There are many things that are out of our control, but one thing that remains within our control is the QUALITY of that time, and aerobic exercise, specifically the promotion of a healthy-addictive habit like cycling, is a fantastic way to enhance the quality of anyone’s life, especially here in Southern California. (But keep that sunscreen close!) Cycling is a means for many people to make lasting, impactful habitual changes in their lives, and I am always so thrilled to hear of people who got back into, or started cycling just to partake in Pedal the Cause.

Quality and Speed of Research Funding
A lot of cancer charities give money to research, though some give only a fraction, and some give none at all, benefitting from the illusion of giving to research. Pedal the Cause gives all proceeds to cancer research in San Diego. It funds the type of collaborative, high-risk, high-reward research that is needed to make a dent in cancer. There is also the aspect of time: Federal funding usually requires years of preliminary research to even get within a country mile of any grant money, making it nearly impossible for innovative research to get funded. As the federal science budget continues to fall, this trend is expected to continue, undermining scientific innovation and discovery. Pedal the Cause completely sidesteps this process and directly funds very promising projects.

Community
Pedal the Cause forces one to walk outside their comfort bubble and engage new people. I had the incredible fortune of being able to use Pedal the Cause fundraising as a bit of an icebreaker to get to know people at my new company, Epic Sciences. To make a long story short, I embarked on a fundraising campaign that involved getting many of my friends, old and new, to donate between $1 and $5 for every time I managed to go up and down Torrey Pines Grade in 5 hours. It was a LOT of fun and a great challenge. More here. I would like to give a huge thank you to my colleagues at Epic Sciences, who provided the lion’s share of donations for fundraising. There really is no shortage of generous, driven, empathetic, genuine people in the cancer / oncology community here in San Diego. It is my hope that Pedal the Cause will continue to grow, and attract more wonderful people to this burgeoning regional cultural event.


Image: The start line, day one. Cancer researchers and caretakers have green armband, cancer survivors have the bright orange helmets. Photo: A.Czapracki

Written by Ryon

September 28th, 2014 at 8:53 pm

Posted in Science Blog

The Epic Window: Circulating Tumor Cells and the Liquid Biopsy

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14 July 2014

Dear Friends and Family,

I’d like to offer a life-update style post (I’ve been a bit off the radar, sorry!). In the span of the last 90 days the following events happened:

1) I defended my PhD
2) Job applications and interviews
3) I began work at Epic Sciences

The short version is that, after a tumultuous last several months (years?) of my PhD, and the job interview process, I have found myself in a high-energy environment surrounded by diversely talented, innovative, genuinely cool, down to earth people all working together to change the face of oncology. I guess you could say I’m a little excited.

Image: a circulating tumor cell (red) from a profile on Epic Sciences in Discover Blogs

To illustrate challenges in oncology, a quote came to mind from the Emperor of All Maladies:

Specificity refers to the ability of any medicine to discriminate between its intended target and its host. Killing a cancer cell in a test tube is not a particularly difficult task: the chemical world is packed with malevolent poisons that, even in infinitesimal quantities, can dispatch a cancer cell within minutes. The trouble lies in finding a selective poison—a drug that will kill cancer without annihilating the patient. Systemic therapy without specificity is an indiscriminate bomb. For an anticancer poison to become a useful drug, Meyer knew, it needed to be a fantastically nimble knife: sharp enough to kill cancer yet selective enough to spare the patient. – Siddhartha Mukherjee

There has been a wave of new anti-cancer therapies approved by the FDA in the last 5 years, many of which have been touted as ushering in the era of precision medicine. These therapies exploit small molecular discrepancies between cancer cells and healthy cells. The problem is, not all cancers have all the same vulnerabilities and the landscape is incredibly diverse, so much so that leading personalized oncology proponents like Dr. Razelle Kurzrock of UCSD refer to use the metaphor of an individual patient’s cancer molecular profile being as unique as snowflakes, and the correct combination of therapies for every patient might be equally unique.

These precision therapies need informed molecular roadmaps, so patients can receive therap(ies) most suited to them. Currently, this requires tissue samples for requisite molecular analyses. However, tissue biopsies are highly invasive to patients, and longitudinal sampling of how an individual patient’s cancer evolves resistance is nearly impossible with current technology.

The process by which the seeds of tumors establish into metastatic niches (i.e. what causes 90% of mortality from solid tumors) involves transit through the blood, which offers an opportunity for molecular characterization of these cells through a routine blood draw. For years I’ve been very interested in this process, so much so that I did a PhD in this area of research!

The last few years have seen an expanded interest in these circulating tumor cells (CTC’s), as new technologies have emerged to capture and analyze them. This is no easy task; it is literally akin to finding one in one *billion* cells in the blood. About a year ago I became aware of the CTC detecting technology of Epic Sciences. To make a long story short, I recently started working to apply circulating tumor cell (CTC) detection and characterization technology for use in guiding oncology clinical trials.

Image: The Scientist recently produced an overview of CTC detection technologies featuring Epic Sciences

As I alluded to before, tissue sampling of tumors in a cancer patient is highly invasive. No one likes being cut up or prodded, probably just slightly less so than having to get an MRI or PET scan. All of the aforementioned require a trip to a hospital, and a lot of the patient’s and health professionals’ valuable time. Advanced cancer patients might also be too sick for these means of examining their cancer, hindering decisions about what therapies to give (or not to give) or what other measures would be most ethical and humane for the patient and their family.

Blood draws, on the other hand, are minimally invasive, and can be performed even at a local clinic. Blood draws can also be performed frequently; it would be unthinkable to perform a tissue biopsy or a PET scan on a cancer patient twice a month!

While the mere presence of circulating tumor cells gives clues to the stage and progression of a patient’s cancer, the real value is in the molecular and genetic characterization of CTC’s. An immensely unmet need in oncology diagnostics and therapy is a means to confront the intratumor heterogeneity that exists within an individual patient’s disease. A patient’s tumor(s) can be very genetically diverse in both location and time and it’s powerful (and in my opinion pragmatic) to have clues about the cancer cells that can cause the most harm to the patient: the ones that make their way into the blood.

Molecular characterization of CTC’s is a fantastic companion to targeted anti-cancer therapies, and I am thrilled to work as part of a team developing the “Liquid Biopsy” for oncology. I have no reservations saying that I am genuinely excited to get out of bed every morning, and I consider myself a very fortunate man to be able to pursue my passions.

If you have read this far I thank you, dear reader. More (meditations) to come!

Ryon

Written by Ryon

July 14th, 2014 at 6:51 am

Posted in Science Blog

How The Liquid Biopsy Could Speed Up Oncology Clinical Trials

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5 May 2014

The realization of Precision Oncology involves developing many low-toxic therapeutics to specifically target genetic weak points in a patient’s cancer. The requisite technology for tumor genomic analysis will likely not be a limiting factor in a few years’ time, especially with the advent of sequencing platforms like HiSeq X Ten by Illumina. The remaining rate-limiting step is the clinical trial phase; clinical trials are immensely expensive to conduct, and measures that can reduce the costs (and time) of oncology clinical trials will allow new molecular scalpels to reach the clinic at a quicker pace.

The pivotal I-Spy1 trial (1) established a strong correlation between observed radiographic reduction of tumor size in the neoadjuvant (before surgery) setting, and long-term survival irrespective of surgery:

Primary objectives were to evaluate whether response to therapy—as measured by imaging (magnetic resonance imaging [MRI] volume) response and pathologic complete response (pCR)—would predict recurrence-free survival (RFS), overall and within biologic and imaging subsets.

I-Spy1 provided the ethical framework for use of radiographic imaging pCR as a surrogate for Survival, and opened the door for neoadjuvant testing of new targeted therapies. I-Spy1 paved the way for the transformative I-Spy2 clinical trial in progress (2). The result is a roughly six-month knowledge turn, instead of a knowledge turn on the order of magnitude of years.

However, radiographic / pathological monitoring of tumor burden is far from optimal. There is a level of subjectivity and noise that can flummox even the most skilled pathologist / radiologist. Also, mammograms, CT Scans, MRI’s are all highly invasive procedures, and very expensive ones at that. The use of these scanning techniques is a contributing factor to the immense cost of clinical trials in oncology.

The Liquid Biopsy has great potential for cancer diagnosis, risk assessment, and therapy. Its advantages are many: compared to more traditional forms of tumor monitoring like PET, MRI, x-ray and mammogram, a blood draw is much less invasive to the patient with much greater ease of re-biopsy and longitudinal monitoring, and potentially much less expensive. But, its technological hurdles are great. That said, they are not insurmountable, and it’s an area of technology that I can see greatly helping many facets of oncology.

Retrospective analyses indicate that numeration of circulating tumor cells (CTC’s) can be a strong prognostic factor, and might be able to predict tumor relapse and / or provide clinically actionable genetic and phenotypic information (3-5).

Perhaps CTC detection technology could be adapted for use in neoadjuvant monitoring of tumor burden? Would a clinical trial similar to I-Spy1, except using a CTC metric in lieu of radiographic tumor size reduction, enable the introduction of less invasive disease monitoring that might shorten clinical trial length and reduce cost? Could this enable a quicker turnaround for therapies to find their way into the clinic?

In the adjuvant (after surgery) setting, might a longitudinal increase in CTC burden indicate impending relapse? Such an increase in CTC number (or perhaps another metric?) could be detectable long before metastatic outgrowths become visible via PET, MRI, X-ray, etc. CTC’s could provide a quicker endpoint for clinical trials? For this to happen, a prospective clinical trial could be structured to establish longitudinal CTC-based metric (such as CTC number, gene expression, size, density, morphological shape, etc.) that strongly indicates impending relapse. Such information could then be used to reduce knowledge turn time for adjuvant clinical trial results, not to mention spare patients from additional chemotherapy for which their cancer is refectory, and begin alternative therapeutic regiments before establishment of radiographically visible tumors.

Ryon

References:

1. Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Sep 10;30(26):3242-9. PubMed PMID: 22649152. Pubmed Central PMCID: PMC3434983. Epub 2012/06/01. eng.
2. DeMichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, et al. Developing safety criteria for introducing new agents into neoadjuvant trials. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013 Jun 1;19(11):2817-23. PubMed PMID: 23470967. Epub 2013/03/09. eng.
3. Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast cancer research and treatment. 2013 Jan;137(2):503-10. PubMed PMID: 23271327. Epub 2012/12/29. eng.
4. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013 Feb 1;339(6119):580-4. PubMed PMID: 23372014. Epub 2013/02/02. eng.
5. Friedlander TW, Premasekharan G, Paris PL. Looking back, to the future of circulating tumor cells. Pharmacol Ther. 2014 Jun;142(3):271-80. PubMed PMID: 24362084. Epub 2013/12/24. Eng.

Edit 5/16/2014: Embarrassing spelling errors

Written by Ryon

May 5th, 2014 at 7:01 pm

Posted in Science Blog

D Fence: My PhD Finale

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28 April 2014

Dear Reader,

The primary focus of the last five years of my life has been the pursuit of a PhD, culminating with my PhD dissertation and defense. A week ago I defended my PhD and was awarded a Doctor of Philosophy in Biomedical Sciences, more colloquially known as a “PhD” or “doctor of science.” I’ve decided to coalesce some thoughts and impressions into something resembling a narrative on the process.

Images: On April Fools’ Day, three weeks before my PhD defense, I sent my good friend Eric Murphy an email: “Hey Eric, I’ve attended a few PhD defenses, but I’m still at a loss whether this would be proper attire?” and included a link to the image below. His response was short: “I’m doing it.” Being April Fools’ Day, the mischievous ambiguity of his response made me unsure whether he was actually planning something. Following the vein of mischievous ambiguity, I opted to not ask him to clarify, and he showed up to my PhD defense with, yes, a D Fence. Friends and family in attendance signed the D Fence after the talk.

The dissertation is a written document describing any and all of my even remotely meaningful work from my PhD. It included some published work, and some work that has not yet been published. I wish I could go into detail about the work I’ve spent several years of my life performing, but some of it needs to go through peer review before I can open it up to the world. C’est la vie.

To complete a PhD, one must host a defense, or public lecture followed by questions by curious specialist and non-specialist minds alike. The public lecture is the first formal occasion for a new doctor to open up their research, ideas and insights to society, to be pondered and questioned by anyone.

More practically, a PhD defense is the final meeting between the PhD candidate and their thesis committee. The main difference from previous meetings is that the public is invited to attend and interrogate the logic, reasoning, research, and knowledge of the PhD Candidate. The public lecture must make something highly esoteric understandable to curious non-specialist minds. But, the talk must remain technical enough to satisfy the Thesis Committee as well. It’s also a rare chance for a PhD Candidate to display their work to friends and family, and making a presentation that can meet all of these demographics is no easy task.

I have many friends and family in the area, many of whom I’ve had to somewhat neglect in my long hours (years?) pursuing new knowledge through research. It’s entirely possible for a PhD candidate to have very few people attend their defense, but where’s the fun in that? I had given many scientific talks to scientists, but rarely to the audience I was expecting. I saw it as a tremendous opportunity to practice my presentation skills, and perhaps have some fun in the process. I’m not referring to a hedonistic, lost-in-the-moment type of enjoyment, but the rare, fleeting satisfaction of doing something well, wrought by blood, sweat and tears.

After all, my original reasons for pursuing medical research were because I wanted to learn to wield the tools of science to have a shot at making a small contribution to medicine. Medicine is a physical manifestation of humanity’s will to live longer and more free of physical ailments and pain. The last century has seen a significant maturation of the relationship between medicine and science, the process by which we reproducibly uncover and define the way the world works. In tandem we can do incredible things like cure infections, eradicate communicable diseases, and make a dent in perhaps the most difficult of diseases to treat: cancer.

Image: Dated to 2600 BCE, the Edwin Smith Papyrus is an ancient Egyptian combination of surgical trauma manual with recommended therapies for fractures, dislocations, lacerations, infections, etc. Among the nearly 50 cases are two describing cancer, for which there was no recommended therapy. The ancient Egyptians clearly recognized cancer as a very difficult disease to treat, perhaps also recognizing the futility of trying to treat it with their medical tools at the time; that intervention was worse than leaving patients to slowly perish. Image courtesy U.S. National Institutes of Health

Along this theme, I dedicated the first chapter of my dissertation to the history of cancer metastatic theory from ancient times until the 20th Century: from fossilized clues about cancer metastasis to the 4700 year old written case studies on cancer patients, to Hippocrates, Galen, Paget, Halstead, and Fisher. At some point in the future I hope to be able to reproduce (with permission) this chapter of my dissertation here on my blog.

I opened my defense talk with a short historical context on cancer, stressing that ancient societies clearly recognized cancer as a very difficult disease to treat. Hippocrates is credited with coining the term “cancer” because he likely recognized the ability of it to crawl throughout a cancer patient, or the physical appearance of autopsied tumors reminded him of a crab. He is also credited with the term “Metastasis” which translates loosely to “dislodgment” or “to be set free.”

For visceral effect, I also included a PET scan of an advanced stage cancer patient (to the right, courtesy uchicago.radiology.edu) with metastatic tumors throughout the body. I then asked my audience to imagine being a surgeon tasked with removing the tumors with a scalpel, stressing the difficulty in treating advanced disease, and how imperative it is for us to understand the process by which this happens so we may target it in means more precise than, well, a surgeon’s scalpel.

I really wish I could go into details about my talk from this point out, but as I mentioned before some of the data has not yet been published, and even more is not yet available via open access (i.e. the publications are owned by entities that charge a fee to the public to view). A discussion on the merits and pitfalls of the antiquated publication model and its (mal?)adaption to 21st century medical research is warranted, but perhaps not here right now.

The abbreviated version of the rest of my talk: Cells have mechanisms that allow for recognition of their physical surroundings and biological zip codes in the body. The means by which they interpret these signals and decide to commit cell suicide or to migrate and grow are integral to the behavior of cancer cells, and at the center of this is my favorite protein: Caspase-8. Through rigorous experimentation employing recombinant protein biochemistry, cell culture models and experiments in vivo, I demonstrated how this protein can play a dual role in cancer malignancy. My research model suggests that this behavior might be toggled by combining two yet-to-be-tested-together classes of drugs that are currently in the clinic and in late phases of clinical development.

Image: A slide from my talk, introducing the concept of metastasis as a multi-step process with hurdles for a cancer cell at every step using very crude illustrations.

Cancer is actually a group of many heterogeneous diseases with overlapping etiology and behavior. My research alone is a far cry from a “cure.” Medical research is the combined efforts of thousands (millions?) of scientists past and present, and my work builds heavily upon work performed by those that came before me. It’s a tremendous honor and privilege to take part in this tradition. By communicating my results and ideas, I am closing a small piece of that loop and contributing (a very small part) to this process.

On a personal side, perhaps the most important and practical thing I have learned in the process is that, after five years of blood sweat and tears (and a healthy helping of head banging) I want some more. I have tested the depths of my motivations and I have found that I am indeed very deeply passionate about using science to improve the physical well-being of cancer patients. There are many times where I could have thrown in the towel, but at every hurdle and hill in my way I found motivation to continue. I remain easily excited by new prospects and developments in science as they pertain to oncology, and when I grab my morning coffee I often get distracted by reading scientific papers and oncology clinical trials results.

In terms of my career, I am allowing myself to be guided by the onus of finding the most impactful, efficient way to improve cancer diagnosis, risk assessment, and therapy. I am currently exploring several options in academia and the biotech industry toward these ends.

If you’ve made it this far I thank you, dear reader.

Sincerely,
Ryon

Written by Ryon

April 28th, 2014 at 10:44 am

Posted in Science Blog

Precision Oncology Needs Neoadjuvant Clinical Trials like I-SPY2

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4 March 2014

The emerging view of cancer is an increasingly diverse set of rare diseases with overlapping etiology and molecular drivers (1). The evolving definition of personalized oncology centers on the development and vetting of many specific, targeted, low-toxicity molecular scalpels that can be used individually or in combinations to tailor a patient’s cancer treatment. The bottleneck of drug development is the testing phase, and there are numerous barriers to novel chemotherapeutic introduction to the clinic.

The I-SPY2 trial has received a lot of press lately, and rightfully so: it’s a bayesian study designed to adaptively match patient genotypes of appropriate therapies in a rotating 5-arm clinical trial that can quickly take on a new agent once one of the test arms graduates, ready for Phase III trials that (theoretically) have a might higher chance for success, with fewer patients (2, 3). The trial has been engineered to make cancer drug trials quicker and less expensive, and more information can be found here.

The I-SPY2 trial is co-directed by Laura Esserman, who gave an illuminating talk at the UCSD Moores Cancer Center last week. Most targeted therapies are tested in clinical trials in heavily pre-treated patients in the metastatic setting, and often without molecular biomarkers. Agents tested in the metastatic setting often see a 2-4 year knowledge turn, while those in the adjuvant setting often come with a 6-9 year knowledge turn. This is simply too slow (and uses too many patients and is too expensive) to realize the vision of personalized oncology.

In the neoadjuvant setting (pre-surgery, chemo-naive patients) the turnaround can be much faster. Instead of disease recurrence, the trial readout is volumetric change in tumors. Tumor samples are subject to panomic (genomic, proteomic, methylomic, etc) analysis before and after neoadjuvant therapy, enabling post-therapy clues to efficacy or failure of tested agents. While this sounds straightforward, this is not the norm for current oncology clinical trials, especially ones for targeted therapies. The reasons for this are beyond the scope of this post. There has been an extreme paucity of information for why certain drugs do not work, and very limited information on what –omics background produce responders.

While pre-operative administration could permit greater organ conservation in the patient, I am also interested in this approach for two additional reasons:

1) Chemotherapy-naive patients might be less susceptible to drug resistance out of the gate. Many drug resistance mechanisms are shared, and patients will not have been weakened from systemic chemotherapy in the neoadjuvant setting (4, 5).

2) Surgery is a highly invasive procedure that damages tissue, releasing cytokines and growth factors that can promote inflammation and tumor growth (6).

The neoadjuvant is a better stage to test for agent efficacy, and opens the door to glimpses of tumor biology that might enable more curative approaches. The neoadjuvant drug administration combined with panomics approaches could be a boon for the emerging “Rapid Learning Precision Oncology” paradigm proposed as part of “Personalized Oncology 3.0″ by Shrager and Tenenbaum (7). Eventually, it may be possible to consider each patient encounter as an experiment, with each additional “experiment” better informed than the last.

I-SPY2 has already graduated two agents to Phase III trials: the small molecule dual HER2 and EGFR inhibitor Neratinib, and the PARP inhibitor Veliparib. The speed at which they passed through Phase II trials is encouraging. Because the trial actively adapts with genotype efficacy, it’s anticipated that Phase III trials will have a greater chance of success. I will be watching this with great anticipation, and at this point in time I am skeptically optimistic about I-SPY2. We need more bullets, big or small, and every new target and every new agent adds another small step toward realizing the vision of personalized oncology.

Ryon

References:

1. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013 Oct 17;502(7471):333-9. PubMed PMID: 24132290. Epub 2013/10/18. eng.
2. Berry DA. Adaptive clinical trials in oncology. Nature reviews Clinical oncology. 2012 Apr;9(4):199-207. PubMed PMID: 22064459. Epub 2011/11/09. eng.
3. DeMichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, et al. Developing safety criteria for introducing new agents into neoadjuvant trials. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013 Jun 1;19(11):2817-23. PubMed PMID: 23470967. Epub 2013/03/09. eng.
4. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013 09/19/print;501(7467):346-54.
5. Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nature medicine. 2013 Nov;19(11):1381-8. PubMed PMID: 24202391. Epub 2013/11/10. eng.
6. Costanzo ES, Sood AK, Lutgendorf SK. Biobehavioral influences on cancer progression. Immunol Allergy Clin North Am. 2011 Feb;31(1):109-32. PubMed PMID: 21094927. Pubmed Central PMCID: PMC3011980. Epub 2010/11/26. eng.
7. Shrager J, Tenenbaum JM. Rapid learning for precision oncology. Nature reviews Clinical oncology. 2014 Feb;11(2):109-18. PubMed PMID: 24445514. Epub 2014/01/22. eng.

Written by Ryon

March 4th, 2014 at 3:26 pm

Posted in Science Blog

New Publication, Dissertation Approved, and Histology

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18 February 2014

It’s been a busy month! Well, most months are busy, but this one has been especially so, and I have some good news to show for it:

1) I am pleased to announce that my review article “Caspase-8 as a Regulartor of Tumor Cell Motility” has been published in Current Molecular Medicine and is available on PubMed.

2) About a week ago I had my pre-thesis defense meeting with my Thesis Committee. After a grueling two hour meeting my Committee Chair gave their verdict: “We are pleased with your progress, we accept your proposed graduation timeline and would like a draft of your dissertation in six weeks’ time.” Looks like I’ll be defending my thesis in the spring! I have not yet set a date, but it’s most likely going to be mid-May.

3) On top of all of that excitement I have been in the midst of my Med Into Grad program. It’s hard to appreciate the nuances and challenges of clinical oncology from the lab bench, and there are so many things that I see on a daily basis that could be aided with new technology. Often, the applications are not groundbreaking or miraculous or ideas that come down from the sky on sunbeams with chariots of angels singing a chorus; they are often subtle, but the sum of all of small innovations will aid modern oncology.

For instance, today I heard a surgeon describe being mid-surgery deep in the peritoneal cavity, his patient open on the operating table. He came across a lesion that looked very much like fibrosis, but was later revealed to be tumor after analysis of biopsy that he sampled just to be sure. A team of physicians then discussed how to move forward on the patient, who was still recovering from surgery with residual tumor cells remaining.

In another instance, a minor stir almost ensued when a patient was staged (via histology) as having a low-grade primary ovarian tumor, when it was more low-ish. The distinction matters tremendously, as the high grade (and more common) tumors will receive systemic, and sometimes preoperative, chemotherapy along with surgery, while the low grade tumors will be treated with surgery alone. The decision to give systemic chemotherapy is not taken lightly by clinical oncologists, and they absolutely need the most un-ambiguous information possible to do be the most effective with the least amount of harm.

I want to find out how subjective and reproducible the measures are that are currently used for diagnosis and guidance of treatment. I want to find means for emerging technology to help remove ambiguity in diagnosis and aid treatment. Could the emerging sequencing technologies and avenues like liquid biopsy provide a better means to asses tumor burden, extent of vascular invasion and prognostic response to existing and emerging therapies? Could this provide a more precise means of who needs what therapy?

In less than a week I’ll be starting my clinical rotations with histology. I’ll be observing how pathologists grade tumors and what sort of clinically relevant information is gleaned from microscopic observation of tumor samples, and how precise and / or subjective such measures are. It should be fun!

Ryon

Written by Ryon

February 18th, 2014 at 6:26 pm

Posted in Science Blog

Heterogeneity in clinical molecular profiling: a case study

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9 January 2014

Happy New Year! This week continues my Med Into Grad clinical exposure, and last night I was privileged to attend Molecular Tumor Board at the UCSD Moores Cancer Center.

Tumor boards are weekly meetings where clinical oncologists discuss their patients and solicit opinions of their peers and others in attendance.  Meetings usually cluster cases together by organ type, i.e. breast cancer.  To address the challenges of the recent flood of new molecularly targeted chemotherapeutics to the clinic, about a year ago the Molecular Tumor Board began, drawing attendance of about 15-20 clinical physicians as well as pathologists, radiologists, genetic counselors, and a few research scientists. It’s an honor for me to attend; many attending scientists have at least some gray hair. I could wax poetic about witnessing the dawn of genetically tailored medicine in front of my eyes, but I’ll spare you, dear reader.

The cases are presented with information like age, date of diagnosis, treatment history, and for molecular tumor board, molecular profile as well. Yesterday the case was presented for a woman with malignant colon cancer. Unlike every other case I’ve seen presented, the patient had molecular profiling performed by no less than five different diagnostic centers: Foundation Medicine, Caris, Clarient, Consultive Proteomics, and Oncopath.

The tests range from immunohistochemical to whole exome sequencing, so variability between the tests would be expected. Also, sample biopsies are from colon, secum, peritoneum and lymph node over a two year period, representing differing geographical and temporal snapshots of what is already (assumed to be) a heterogeneous, evolving disease. Perhaps it is not surprising that among the 15 actionable targets indicated by these tests combined, only three of these targets were reported by more than one test.

After a few minutes of discussion, another shared “target” was revealed with similar mRNA elevation consistent between two tests, but was included in only one of the two official reports because of different thresholds of significance used by different companies.

So, what are the actual actionable targets for this patient?!? It would be easy to dismiss this as gibberish, but what this does represent, however, are five example clinical information scenarios of the same patient. Depending on the time of diagnosis, previous therapy, location of biopsy, and preference of diagnostic center, any of these five test results could have reasonably found their way to this patient’s oncologist’s iPad.

Instead, these are all presented for one patient, underscoring the tremendous challenge posed to the clinical translation of this knowledge for personalized medicine, likely representing not only highly heterogeneous disease, but highly heterogeneous therapy courses, and heterogeneous outcomes as well.

So, why not get this five dimensional testing done for all cancer patients? There are a few barriers. The first is cost: each test is upwards of $5000. The second is ethical: tissue biopsies are invasive, and multiple biopsies are only feasible for patients with highly accessible disease.

How will we standardize this knowledge? Should we? To what degree? How should it be presented? What sort of continuing education could be necessary / appropriate for clinical oncologists at centers without access to a molecular tumor board?

I will be pursuing these questions as Med Into Grad continues!

Ryon

(back to ryongraf.com)

Written by Ryon

January 9th, 2014 at 5:03 pm

Posted in Science Blog

FDA regulating hype? What about supplements and e-medicine?

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6 December 2013

Commentary

As a follow-up to last week’s post, I can’t help but wonder about the future of the FDA, more than the future of medical genomic testing.

The FDA appears to have its beef not with sequencing, per se, but the hype of the interpretations of that sequencing. As far as genomic sequencing goes, it would be unreasonable for the FDA to prevent people from sequencing their own genes, and this is not what it’s doing for the time being. The real beef that the FDA has with 23andMe was the interpretation of that sequencing, taking what has been called a “paternalistic” role to vet / regulate the quality of information that could directly affect the actions taken by patients.

Along those lines, why not intervene and regulate online health info amalgamations like livestrong.com and WebMD.com? Is this not medical diagnostic hype? (see image)

This point was touched upon by Rahul Rekhi in The Guardian:

And what of services like WebMD – the hypochondriac’s haven – which offer patients checklists by which to self-diagnose their perceived symptoms? Do these not pose similar public health concerns? Yet, they persist largely uninhibited.

While half a million customers for 23andMe is nothing to laugh at, it still pales in comparison to the massive tide of people making significant personal health decisions based off ill-vetted pseudoscientific information on the internet. If the FDA wants to expand its reach and do the maximum public good, perhaps they should step in here, or perhaps the poorly regulated, multi-billion dollar supplements industry? An anti-cancer drug needs 15+ years and multiple stages of clinical trials and upwards of a billion dollars to show efficacy by our standards, but nothing is preventing snake oil salesmen from marketing homeopathic water to promote “vitality” to cancer patients.

Also, companies like 23andMe could easily make themselves over in countries without an overly paternalistic FDA. Its rather easy to sidestep regulatory oversight of transporting biological specimens (like cheek swabs) across international boundaries: one could have their genome sequenced in California and instantly uploaded the Cloud with something like Illumina’s BaseSpace and immediately have it analyzed by medical genomics teams in India, Singapore, etc.

The FDA has put its finger firmly in the hole in the dam, but it looks like the rising tide of genomic sequencing will soon spill it all over anyway. The plot thickens…

Written by Ryon

December 6th, 2013 at 4:31 pm

Posted in Science Blog

23andMe, the FDA, and evolving science ethics

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27 November 2013

I’ve got a thesis to write, manuscript to edit, and a pesky microscope problem to work around, but I just cannot help but follow the current discussions surrounding the battle between 23andMe and the FDA. There’s a LOT of hype and charged discussions going on in social media at the moment, and I’ve had the pleasure of watching it all unfold. All in all, I have seen some very healthy ethical discussion on many fronts. I thought I’d share a few enlightened points I’ve come across.

First, came the announcement:

The actual letter from the FDA is a fantastic read: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm376296.htm

Your company submitted 510(k)s for PGS on July 2, 2012 and September 4, 2012, for several of these indications for use. However, to date, your company has failed to address the issues described during previous interactions with the Agency or provide the additional information identified in our September 13, 2012 letter for (b)(4) and in our November 20, 2012 letter for (b)(4), as required under 21 CFR 807.87(1). Consequently, the 510(k)s are considered withdrawn, see 21 C.F.R. 807.87(1), as we explained in our letters to you on March 12, 2013 and May 21, 2013.  To date, 23andMe has failed to provide adequate information to support a determination that the PGS is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it; no other submission for the PGS device that you are marketing has been provided under section 510(k) of the Act, 21 U.S.C. § 360(k).  {emphasis added}

Matthew Herper in Forbes gives a great introduction to what is a highly nuanced ethical debate quickly becoming a macrocosm of a battle between 23andMe and the FDA:

I’d like to be able to start here by railing against our medical system, which prevents patients from getting data about our own bodies because of a paternalistic idea that people can’t look at blood test results, no less genetic information, without a doctor being involved or the government approving the exact language of the test. I’d like to be able to argue that the Food and Drug Administration is wantonly standing in the way of entrepreneurism and innovation by cracking down on 23andMe, a company that is just trying to give patients the ability to know about their own DNA, to understand their own health risks, and to participate in science.

I wish that was the story I’m about to write, but it’s not, and it all really comes down to one fact in the FDA’s brutally scathing warning letter to 23andMe, the Google GOOG +0.36%-backed personal genetics startup. It’s this quote from the letter by Ileana Elder, in the agency’s diagnostics division: ‘FDA has not received any communication from 23andMe since May.’

more here: http://www.forbes.com/sites/matthewherper/2013/11/25/23andstupid-is-23andme-self-destructing/

The blog Genotopia makes some very important distinctions about what the FDA is trying to regulate:

We must be clear that the FDA letter does not prohibit 23andMe from selling their test. It demands they stop marketing it. The difference may not amount to much in practice—how much can you sell if you don’t market your product?—but the distinction does help clarify what is actually at stake here. FDA is not attempting to instigate a referendum on the public’s access to their own DNA information. They are challenging the promises 23andMe seems to make. This is, in short, not a dispute about access, but about hype.

The company seems to promise self-knowledge. The ad copy for 23andMe promises to tell you what your genome ‘says about you.’ ‘The more you know about your DNA,’ they trumpet, ‘the more you know about yourself.’ On one level, that’s perfectly, trivially true: your genome does have a lot to do with your metabolism, body structure, how you respond to disease agents, and so forth. The problem is, we as yet know very little about how it all works. The 23andMe marketing exploits a crucial slippage in the concept of ‘knowledge,’ which FDA correctly finds misleading. In short, the marketing implies a colloquial notion of knowledge as a fixed and true fact, while the science behind the test is anything but.

Genotopia continues:

…The 23andMe product, like every genome test, provides probabilities of risk, not mechanisms. Probabilities are messy and hard to understand. They carry an almost irresistible tendency to be converted into hard facts. If you flip a coin 9 times and it comes up heads every time, you expect the next flip to come up tails. And if you get heads 49 times in a row, the next one has got to be tails, right? Even if you know intellectually that the odds are still 50:50, just like on every previous flip. You can know you have a particular gene variant, but in most cases, neither you nor anyone else knows exactly what that means. Despite the language of probability that dots the 23andMe literature, their overall message—and the one clearly picked up by many of their clientele—is one of knowledge in the colloquial sense. And that is oversell.

…the 23andMe test is being sold directly to individuals who may not have any knowledge of genetics. The tendency to convert risks into certainty is higher than ever. The knowledge they sell is a set of probabilities, and further, those probabilities are not stable. The consumer may not—indeed probably doesn’t—appreciate how much we know, how much we don’t know, and how much we don’t even know we don’t know. The company claims to be selling knowledge but in fact they are selling uncertainty.

More here: http://genotopia.scienceblog.com/379/23andme-fda-and-the-history-of-hype/

David Dobbs’s NEURON CULTURE has created a fantastic list of diverse, intelligent commentary on the ethics, regulations, and science surrounding the current story: http://daviddobbs.net/smoothpebbles/feds-muzzle-23andme-decide-public-best-be-ignorant-about-genetics/

He also offers some of his own commentary, perhaps advocating that a little messiness in the system must be weighed against the potential for positive impacts:

But do those apparently rare errors inflict more harm than the sorts of errors our medical system makes every day? Do they inflict more harm than a lack of information about important risk genes inflict? Does any harm done outweigh the great good that people gain from having inexpensive access to lots of information about medical risk?

A person learning the status of hundreds of genes of medical interest (along with information about their ancestry) with a simple spit-test may learn much actionable information — not to mention an education about genetics — that would otherwise depend on … what? Expensive access to doubtless heavily marked-up genetic tests prescribed by physicians and executed by companies happy to charges hundreds of dollars per gene? We need more such information; not less. I pray this will soon be reversed.

Lastly, there is the discussion about whether the FDA is hindering what could be a fantastic new dawn of public interest in science, not just for of un-health aversion, but just for the sake of inquiry, curiosity and education in itself. I have to admit, that this arena plucks a special chord in my heart. At the very least, I’m so glad to see these types of discussions continue, and move forward general public interest in science and genetics.

Ryon

Written by Ryon

November 27th, 2013 at 1:44 pm

Posted in Science Blog

N of 1 Study Insightful to Prostate Cancer Evolution, Therapy?

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18 November 2013

(back to science blog)

It’s tantalizing (and extremely important) to factor the fourth dimension in cancer: time. Cancer is a microcosm of evolution, the most lethal versions of which are bestowed with an immense reservoir of genetic heterogeneity, providing the raw resources to adapt to changing environments. The physical manifestations of this are the same that thwart treatment: chemotherapy resistance and metastasis (1).

Tumor heterogeneity over time is difficult to study, owing to a rarity in genomics-grade longitudinal samples in cancer patients. Last week I had the pleasure of presenting a curious N=1 study to our weekly journal club here at the Moores Cancer Center. Haffner and colleagues performed genomic and histological analyses on unusually well-preserved specimens collected over a man’s 17 year disease course with prostate cancer (2). (article available for free here)

The ensuing analyses revealed a few interesting pieces of information:

The region of the prostate surveyed that likely gave rise to a wave of lethal metastases 17 years after diagnosis (and radical prostatectomy) was of low histological grade compared to the rest of the prostate tumor region.

The lymph node metastasis removed the same time as the radical prostatectomy differed in molecular signature to the lethal metastases 17 years later, indicating a diverging evolution and suggesting, at least in this patient, that the palpable lymph node tumor did not act as a way station for the lethal, visceral metastases 17 years later in the lung, liver, and thoracic lymph nodes. This gives weight to the “embolization” theory of metastasis in prostate cancer, which posits that lymphatic and hematogenous dissemination are two separate paths, the lethal one being hematogenous. In breast cancer, this distinction was the subject of much debate until clinical trials very clearly demonstrated that aggressive removal of regional lymphatics does not reduce the risk of distant organ dissemination in breast cancer (3, 4). Perhaps the same could be true for prostate cancer? While not “essential” organs, aggressive surgical removal of regional lymphatics is far from innocuous. Even small hints at tumor evolution can glean valuable information for the most effective, least invasive means to treat prostate cancer.

Lastly, the metastatic clones that aggressively arose 17 years after diagnosis were all highly similar in both driver and passenger mutations, indicating a temporally recent progenitor. The questions that I would like to ask are:

Where were these metastatic clones hiding out for 17 years? The patient had multiple gaps without detectable disease. Also, what caused re-immergence from metastatic latency? Why then and not 10 years prior or 10 years in the future? Was there an undetected watershed moment mutation after decades of genomic Russian roulette and genomic instability that enabled the emergence of a lethal clone? Or, were there coordinated changes in many tissues at once that could have given rise to a more favorable environment for metastasis (i.e. perhaps some threshold related to aging)?

These questions cannot be answered with the current study, and I agree with Brannon and Sawyers (5) that N=1 studies could be immensely more powerful if we are able to better transpose genomics to the spatial and temporal disease course of many patients. At this point we have the technology; the real challenges in implementation are clinical and logistical, which can be overcome.

Ryon

References:
1. Klein CA. Selection and adaptation during metastatic cancer progression. Nature. 2013 09/19/print;501(7467):365-72.
2. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. The Journal of clinical investigation. 2013 Nov 1;123(11):4918-22. PubMed PMID: 24135135. Pubmed Central PMCID: PMC3809798. Epub 2013/10/19. eng.
3. Donker M, Straver ME, van Tienhoven G, van de Velde CJ, Mansel RE, Litiere S, et al. Comparison of the sentinel node procedure between patients with multifocal and unifocal breast cancer in the EORTC 10981-22023 AMAROS Trial: Identification rate and nodal outcome. Eur J Cancer. 2013 Mar 19. PubMed PMID: 23522754. Epub 2013/03/26. Eng.
4. Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham DL, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. The New England journal of medicine. 1985 Mar 14;312(11):674-81. PubMed PMID: 3883168. Epub 1985/03/14. eng.
5. Brannon AR, Sawyers CL. “N of 1″ case reports in the era of whole-genome sequencing. The Journal of clinical investigation. 2013 Nov 1;123(11):4568-70. PubMed PMID: 24135144. Pubmed Central PMCID: PMC3809802. Epub 2013/10/19. eng.

Written by Ryon

November 18th, 2013 at 10:11 am

Posted in Science Blog