Three mechanisms of dark selection for ruxolitinib resistance

Last week I returned from the 6th annual IMO Workshop at the Moffitt Cancer Center in Tampa, Florida. As I’ve sketched in an earlier post, my team worked on understanding ruxolitinib resistance in chronic myelomonocytic leukemia (CMML). We developed a suite of integrated multi-scale models for uncovering how resistance arises in CMML with no apparent strong selective pressures, no changes in tumour burden, and no genetic changes in the clonal architecture of the tumour. On the morning of Friday, November 11th, we were the final group of five to present. Eric Padron shared the clinical background, Andriy Marusyk set up our paradox of resistance, and I sketched six of our mathematical models, the experiments they define, and how we plan to go forward with the $50k pilot grant that was the prize of this competition.


You can look through our whole slide deck. But in this post, I will concentrate on the four models that make up the core of our approach. Three models at the level of cells corresponding to different mechanisms of dark selection, and a model at the level of receptors to justify them. The goal is to show that these models lead to qualitatively different dynamics that are sufficiently different that the models could be distinguished between by experiments with realistic levels of noise.
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Dark selection and ruxolitinib resistance in myeloid neoplasms

I am weathering the US election in Tampa, Florida. For this week, I am back at the Moffitt Cancer Center to participate in the 6th annual IMO Workshop. The 2016 theme is one of the biggest challenges to current cancer treatment: therapy resistance. All five teams participating this year are comfortable with the evolutionary view of cancer as a highly heterogeneous disease. And up to four of the teams are ready to embrace and refine a classic model of resistance. The classic model that supposes that:

  • treatment changes the selective pressure on the treatment-naive tumour.
  • This shifting pressure creates a proliferative or survival difference between sensitive cancer cells and either an existing or de novo mutant.
  • The resistant cells then outcompete the sensitive cells and — if further interventions (like drug holidays or new drugs or dosage changes) are not pursued — take over the tumour: returning it to a state dangerous to the patient.

Clinically this process of response and relapse is usually characterised by a (usually rapid) decrease in tumour burden, a transient period of low tumour burden, and finally a quick return of the disease.

But what if your cancer isn’t very heterogeneous? What if there is no proliferative or survival differences introduced by therapy among the tumour cells? And what if you don’t see the U curve of tumour burden? But resistance still emerges. This year, that is the paradox facing team orange as we look at chronic myelomonocytic leukemia (CMML) and other myeloid neoplasms.

CMML is a leukemia that usually occurs in the elderly and is the most frequent myeloproliferative neoplasm (Vardiman et al., 2009). It has a median survival of 30 months, with death coming from progression to AML in 1/3rd of cases and cytopenias in the others. In 2011, the dual JAK1/JAK2 inhibitor ruxolitinib was approved for treatment of the related cancer of myelofibrosis based on its ability to releave the symptoms of the disease. Recently, it has also started to see use for CMML.

When treating these cancers with ruxolitinib, Eric Padron — our clinical leader alongside David Basanta and Andriy Marusyk — sees the drastic reduction and then relapse in symptoms (most notably fatigue and spleen size) but none of the microdynamical signs of the classic model of resistance. We see the global properties of resistance, but not the evidence of selection. To make sense of this, our team has to illuminate the mechanism of an undetected — dark — selection. Once we classify this microdynamical mechanism, we can hope to refine existing therapies or design new therapies to adapt to it.

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Cytokine storms during CAR T-cell therapy for lymphoblastic leukemia

For most of the last 70 years or so, treating cancer meant one of three things: surgery, radiation, or chemotherapy. In most cases, some combination of these remains the standard of care. But cancer research does not stand still. More recent developments have included a focus on immunotherapy: using, modifying, or augmenting the patient’s natural immune system to combat cancer. Last week, we pushed the boundaries of this approach forward at the 5th annual Integrated Mathematical Oncology Workshop. Divided into four teams of around 15 people each — mathematicians, biologists, and clinicians — we competed for a $50k start-up grant. This was my 3rd time participating,[1] and this year — under the leadership of Arturo Araujo, Marco Davila, and Sungjune Kim — we worked on chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. CARs for ALL.

Team Red busy at work in the collaboratorium

Team Red busy at work in the collaboratorium. Photo by team leader Arturo Araujo.

In this post I will describe the basics of acute lymphoblastic leukemia, CAR T-cell therapy, and one of its main side-effects: cytokine release syndrome. I will also provide a brief sketch of a machine learning approach to and justification for modeling the immune response during therapy. However, the mathematical details will come in future posts. This will serve as a gentle introduction.

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Diversity working together: cancer, immune system, and microbiome

After a much needed few weeks of recovery, I’ve found some time to post about our annual IMO workshop held this year on the topic of viruses in cancer. Our group had the challenge of learning about all of the complexities of the human microbiome and its interactions with a cancerous lesion. The human microbiome, in a nutshell, is the ecological community of commensal, symbiotic, and pathogenic microorganisms that live on our inner and outer surfaces including bacteria, fungi, and viruses. The number of cells in the human microbiome is more than 10 times the amount of cells in our bodes (Costello et al., 2009), which means that 2-6 pounds of us is made of, not exactly us, but microorganisms. The microbiome has become a popular topic as of recent, with more than just human-centric studies sparking interest (see links for kittens, seagrass, the University of Chicago’s hospital, and the earth). See the video below for a nice introduction to the microbiome (and the cutest depiction of a colon you will ever see):

The first thing that I learned about the human microbiome is the extreme diversity of the bacterial communities. We have quite unique microbiomes, though they are shared through kissing, similar diets, and among families and pets (Song et al., 2013; Kort et al., 2014)! Further, there are huge discrepancies of the microbial communities that live in our hair, nose, ear, gut and foot (Human Microbiome Project Consortium, 2012). So the challenge to find a project that would address this diverse microbiome and its interaction with cancer in a way that we could test with real data to BOTH answer a clinically-relevant question AND be mathematically modeled in 4 days (what!?) was a little daunting. Good thing we had an epidemiologist and expert in the microbiome (Christine Pierce Campbell), a medical oncologist specializing in head and neck cancers (Jeffery Russell), and an excellent team of biologists, mathematicians, computer scientists, and biophysicists (#teamFecal) ready to rumble.

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Helicobacter pylori and stem cells in the gastric crypt


Last Friday, the 4th Integrated Mathematical Oncology Workshop finished here at Moffitt. The event drew a variety of internal and external participants — you can see a blurry photo of many of them above — and was structured as a competition between four teams specializing in four different domains: Microbiome, Hepatitis C, Human papillomavirus, and Helicobacter pylori. The goal of each team was to build mathematical models of a specific problem in their domain that were well integrated with existing clinical and biological resources, the reward was a start-up grant to the project that seemed most promising to the team of judges. As I mentioned earlier in the week, I was on team H. Pylori — lead by Heiko Enderling with clinical insights from Domenico Coppola and Jose M. Pimiento. To get a feeling for the atmosphere of this workshop, I recommend a video summary of 2013’s workshop made by Parmvir Bahia, David Basanta, and Arturo Araujo:

I want to use this post to summarize some of the modeling that we did for the interaction of H. Pylori and gastric cancer. This is a brief outline — a reminder of sorts — and concentrates only on the parts that I was closely involved in. Unfortunately, this means that I won’t cover all the perspectives that our team offered, nor all the great work that they did. I apologize for the content I omitted. Hopefully, I can convince some other team members to blog about their experience to give a more balanced perspective.

This post also won’t cover all that you might want to know about bacteria and gastric cancer. As we saw earlier, fun questions about H. Pylori span many length and temporal scales and it was difficult to pick one to focus on. Domenico pointed us toward Houghton et al.’s (2004) work on the effect of H. Pylori on stem cell recruitment (for a recent survey, see Bessede et al., 2014), and suggested we aim our modeling at a level where we can discuss stem cells quantitatively. The hope is to use the abundance of stem cells as a new marker for disease progression. In the few days of the workshop, we ended up building and partially integrating two complimentary models; one agent-based and one based purely on ODEs. In the future, we hope to refine and parametrize these models based on patient data from Moffitt for the non-H. Pylori related gastric cancers, and from our partners in Cali, Colombia for H. Pylori related disease.
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From H. pylori to Spanish colonialism: the scales of cancer.

IMO2014Yesterday was the first day of the 4th Integrated Mathematical Oncology Workshop here at Moffitt. This year, it is run jointly with the Center for Infection Research in Cancer and is thus focused on the interaction of infection disease and cancer. This is a topic that I have not focused much attention on — except for the post on canine transmissible venereal tumor and passing mentions of Human papillomavirus (HPV) — so I am excited for the opportunity to learn. The workshop opened with a half-day focused on getting to know the external visitors, Alexander Anderson’s introduction, and our team assignments. I will be teammates with Heiko Enderling, Domenico Coppola, Jose M. Pimiento, and others. We will be looking at Helicobacter pylori. Go team blue! If you are curious, the more popularly known HPV went to David Basanta’s team, it will be great to compete against my team leader from last year. As you can expect, the friendly trash talking and subtle intimidation has already begun.

To be frank, before yesterday, I’ve only ever heard of H. pylori once and knew nothing of its links to stomach cancer. The story I heard was associated with Barry J. Marshall and J. Robin Warren’s award of the 2005 Nobel Prize in Physiology and Medicine “for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease”. In 1984, Marshall was confident in the connection between H. pylori, inflammation, and ulcers, but the common knowledge of the day was that ulcers were caused by things like stress and smoking, not bacteria. The drug companies even happened to have an expensive drug that could manage the associated stomach inflammation, and given the money it was bringing in, nobody was concerned with finding some bacterium that could be cured with cheap antibiotics. Having difficulty convincing his colleagues (apart from Warren), Marshall decided to drink a Petri dish of cultured H. pylori, and within a few days grew sick, developing severe inflammation of the stomach before finally (two weeks after the ingestion) going on antibiotics and curing himself. This dramatic display was sufficient to push for bigger studies that eventually lead to the Nobel prize; I recommend listening to Warren’s podcast with Nobel Prize Talks or his acceptance speech for the whole story.

This is a fascinating tale, but from the modeling perspective, the real excitement of H. pylori and its role in stomach cancer is the multitude of scales that are central to the development of disease. We see important players from the scale of molecules involved in changing stomach acidity, to the single-cell scale of the bacteria and stomach lining, to the changes across the stomach as a whole organ, and the role of the individual patient’s life style and nutrition. These are the usual scales we see when modeling cancer, and dovetail nicely with Anderson’s opening remarks on the centrality of mathematics in helping us bridge the gaps. However, in the case of H. pylori, the scales go beyond the single individual at which Anderson stops and extend to the level of populations of humans in the co-evolution of host and pathogen, and even populations of groups of humans in a speculative connection to a topic familiar to TheEGG readers — the evolution of ethnocentrism. In preparation for the second half of the second day and the intense task of finding a specific question for team blue to focus on, I wanted to give a quick overview of these scales.
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From heuristics to abductions in mathematical oncology

As Philip Gerlee pointed out, mathematical oncologists has contributed two main focuses to cancer research. In following Nowell (1976), they’ve stressed the importance of viewing cancer progression as an evolutionary process, and — of less clear-cut origin — recognizing the heterogeneity of tumours. Hence, it would seem appropriate that mathematical oncologists might enjoy Feyerabend’s philosophy:

[S]cience is a complex and heterogeneous historical process which contains vague and incoherent anticipations of future ideologies side by side with highly sophisticated theoretical systems and ancient and petrified forms of thought. Some of its elements are available in the form of neatly written statements while others are submerged and become known only by contrast, by comparison with new and unusual views.

If you are a total troll or pronounced pessimist you might view this as even leading credence to some anti-scientism views of science as a cancer of society. This is not my reading.

For me, the important takeaway from Feyerabend is that there is no single scientific method or overarching theory underlying science. Science is a collection of various tribes and cultures, with their own methods, theories, and ontologies. Many of these theories are incommensurable.
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Simplifying models of stem-cell dynamics in chronic myeloid leukemia

drugModelIf I had to identify one then my main allergy would be bloated models. Although I am happy to play with complicated insilications, if we are looking at heuristics where the exact physical basis of the model is not established then I prefer to build the simpleast possible model that is capable of producing the sort of results we need. In particular, I am often skeptical of agent based models because they are simple to build, but it is also deceptively easy to have the results depend on an arbitrary data-independent modeling decision — the curse of computing. Therefore, as soon as I saw the agent-based models for the effect of imatinib on stem-cells in chronic myeloid leukemia (Roeder et al., 2002; 2006; Horn et al., 2013 — the basic model is pictured above), I was overcome with the urge to replace it by a simpler system of differential equations.
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Predicting the risk of relapse after stopping imatinib in chronic myeloid leukemia

IMODay1To escape the Montreal cold, I am visiting the Sunshine State this week. I’m in Tampa for Moffitt’s 3rd annual integrated mathematical oncology workshop. The goal of the workshop is to lock clinicians, biologists, and mathematicians in the same room for a week to develop and implement mathematical models focussed on personalizing treatment for a range of different cancers. The event is structured as a competition between four teams of ten to twelve people focused on specific cancer types. I am on Javier Pinilla-Ibarz, Kendra Sweet, and David Basanta‘s team working on chronic myeloid leukemia. We have a nice mix of three clinicians, one theoretical biologist, one machine learning scientist, and five mathematical modelers from different backgrounds. The first day was focused on getting modelers up to speed on the relevant biology and defining a question to tackle over the next three days.
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