Category Archives: Biology/science

It’s “Embrace Your Geekness Day”!

Today, July 13th (I’m still up y’all) is Geekness Day or “Embrace Your Geekness Day” – what better excuse for a quick post on why I am TheCancerGeek (my current username on the internet). I actually didn’t know about this geek celebration day until SingleHop (a cloud hosting company) contacted some geeky bloggers including me, and gave us a couple of prompts for a post on geekdom.

“What makes me a geek?”

My journey into cancer geekdom started as a freshman in college, now almost 10 years ago, when I took a non-majors cancer biology course where I got a taste of basic cancer cell biology, and some insight into certain causes of cancer like genetic factors, environmental causes or oncogenic viruses (HPV and the like).

Fast forward to today. Geekyness about a scholarly topic means a deep and broad interest into something complex yet fascinating and you don’t care whether others share this obsession. To me cancer biology fits that definition – both something that is intrinsically interesting and yet a major societal problem to be involved with finding solutions to.

Even though in the lab, I study a very particular aspect of targeting inflammatory breast cancer, my overall cancer geekiness makes me seem a bit unfocused at times. I love reading about other aspects of cancer biology that span other disease contexts as well – how treatments have evolved over time, new areas of discovery in cancer immunotherapy, cancer metabolism, mechanisms of cancer cell plasticity, genetic screens for new combinatorial strategies etc. The research seems endless at times! I probably spend much longer than the average post doc reading both clinical papers and more translational articles about many topics. One of things I do in my “free” time is volunteer as a science advocate in 2 facebook groups run by the IBC Network. I love being challenged by members to explain something in lay terms, debunk badly written articles about research and especially love it if I’m asked a tough question that I don’t know the answer to — great excuse to go to pubmed or UpToDate and figure it out. Usually I learn more than what I set out to figure out (after all, that is truly what graduate level training is about – not simply knowing a set of facts about the problem you studied). And that’s how it goes when you are a geek – digging and digging yet some more.

“Favorite geek quote”

Confession: I am a quote collector! A few that I like about geeks/geekyness:

“Geeks are people who love something so much that all the details matter.” (Marissa Mayer)


“Being a geek is a great thing. I think we’re all geeks. Being a geek means you’re passionate about something and that defines your uniqueness. I would rather be passionate about something than be apathetic about everything.” (Masi Oka)


“If your culture doesn’t like geeks, you are in real trouble” (Bill Gates)

And finally,

Who is my geek role model?”

I would say none other than Dr Sally Church, of Pharma Strategy Blog (and founder of Icarus Consultants). Like me Sally has broad interests in oncology and it is really fun to discuss new research papers and talks from conferences with her. Even when she admits breast cancer is not her favorite disease site 😉 Not to mention Sally is a discerning user of the latest Apple technology like me! 🙂 #GeeksRule!

So my advice to others who think they might be geeks…. KeepCalmGeek

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“It really shouldn’t be up to a patient to know….”

Today was a slightly less busy Monday than usual since I was at lab for a gazillion hours this weekend (ok slight exaggeration but longer than usual, and got a bit ahead of usual). This meant not only I had time to mull some things over while doing cell culture less hurriedly than usual on a Monday, but I had a little half hour or so before lunch to look at my weekly pubmed email updates.

A new paper in the Annals of Oncology caught my attention since it was a large population on IBC patient outcomes study regarding ~7700 patients diagnosed between 1990 and 2010. This caught my attention because there hasn’t been much written on this lately outside of single institution studies (such as MDACC’s own experience) – which have limitations including positive bias (places with terrible outcomes less likely to write academic papers vs centers of excellence with nuggets to share). Intrigued I read over most of it, and scrutinized the figures/tables. The purpose of the paper was to investigate whether overall outcomes of IBC have improved over time using a national healthcare database called SEER, focusing on stage 3 patients. Just to share a piece of the promising data they show, figure 1 shows a nice positive trend in 2-year overall survival that goes from 50% in 1990 to ~70% in 2010. However as I dug deeper, a few things disturbed me. The data in most of the tables is stratified by year of diagnosis…..a few things that stood out to me.


Figure 1: 2 year overall survival and the years in which selected drugs became used in IBC.

Ok first I have to explain a few things– today’s definitive treatment for stage 3 IBC given with curative intent includes upfront (neoadjuvant) chemotherapy, then a modified radical mastectomy followed by radiation. If HER2 positive, 1 year of Herceptin is included starting concurrently with chemotherapy (finished after surgery). If ER+, 5+ years of adjuvant endocrine therapy appropriate to menopausal status (tamoxifen or aromatase inhibitor) is given after radiation.

Going back to the SEER data – what do these data show? In the most recent 5 year period specifically, only 82% of patients received a mastectomy. 18% rate of breast conserving surgery is unacceptable when IBC is an absolute contraindication to lumpectomy (the reason being since the disease by definition involves the skin, it must go as well as the whole breast!). These surgeries also were not done to today’s standard. In the table there is a section on number of nodes examined. Shockingly, 20.5% had ZERO nodes examined. Mind boggled! Axillary nodal dissection is an important component of comprehensive staging and is considered a very standard step during surgery. While sentinel node dissection (SLND) is becoming more and more considered in other locally advanced breast cancers treated by mastectomy, the role of SLND is still under investigation in IBC. The MDACC surgical team is trying to identify a subset of patients who can be spared the morbidity from axillary dissections yet adequately stage their axilla. However as of today, every patient should have 1 or more nodes examined. Preferably all the level 1 and 2 nodes that the surgeon finds.

Next up – only 51% of patients received radiation. This should be 100%. No excuses – radiation is a very important form of local therapy that has been proven to make a difference in outcomes. Studies of many high-risk breast cancer patients have demonstrated that radiation decreases the risk of loco-regional recurrence by 50-66% – which is a lot when your baseline recurrence risk is as high as it is for most IBC patients.


Figure 2: Data showing less than optimal treatment provided.

Lastly, but not of least importance, is an analysis of outcomes by race. For white patients diagnosed between 2006 and 2010 – the 2-year OS is 75%, whereas among black women it is only 61%. Why is this? Complicated topic – likely both underlying biology as well as factors relating to access to good quality care. Another topic for another day, but just another statistic from the paper that bothered me, and barely commented on by the authors.

So back to the original question are we doing better? Yes statistically the p-values for all the comparison show an increase in outcomes over time. But there is still a lot to do. Clearly triple-negative IBC still lags behind – less than 15% have a pathological complete response and this leads to a median overall survival around 2 years. To do better in TN-IBC, we will not only need to increase pCR rates (perhaps by adding targeted agents to chemotherapy or changing cocktails to take advantage of new knowledge) but also find some adjuvant therapy that is useful to mimic the benefits from endocrine therapy in ER+ disease. What about a vaccine or similar immunotherapy approach as well.

Perhaps it would be best to start with applying what we already know though. Outcomes are best with a multi-disciplinary team working together – good upfront staging (radiologists working hand-in-hand with pathologist to get enough of the correct tissue), optimal chemotherapy (anthracycline+taxane or otherwise) upfront with a competent medical oncologist closely following response. The medical oncologist then handing the patient off to trusted surgical oncologists who will do the CORRECT surgery, get clean margins and then of course a radiation oncologist to mop up any residual local disease with an appropriate dose, frequency and fields based on the individual patients risk factors. It really shouldn’t be up to a patient newly diagnosed with an uncommon, rapidly progressing life-threatening disease to know this stuff. Are you with me?


Source: Dawood S et al, “Survival of women with inflammatory breast cancer: A large population based study”. Annals of Oncology 2014 (in press), article link


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SABCS 2013: What I’m most looking forward to seeing this year

Well the annual San Antonio Breast Cancer Symposium is here and I’m very excited to be here to learn what’s new and upcoming in the world of research and clinical care. I meant to get this post up before I left, but my lab work this weekend had other ideas.   Just a quickie post from the hotel this morning before the sessions start for real this afternoon.

The biggest, most exciting news is that Inflammatory Breast Cancer (IBC) will have its first education session ever at SABCS. It is today at 5:30pm, and is being chaired by MD Anderson’s awesome Dr Wendy Woodward. The other IBC expert speakers are Massimo Cristofanilli and Sofia Merajver.

Looking through the rest of the program briefly, a few themes popped out at me about this meeting. One – this will be a big meeting for TNBC biology. We are no doubt going to hear about new developments in finding new targets, including following up on the relevance of JAK2 mutations (as reported last year), targeting the folate receptor, and cancer stem cell pathways. In addition, we will be hearing more about Celldex’s antibody-drug conjugate, Glembatumumab vedotin(also known as CDX-011) that is being studied in metastatic TNBC, in their new randomized METRIC study. CDX-011 targets TNBCs that overexpress glycoprotein gpNMB, which is involved in aggressiveness of TNBCS (resistance to standard chemotherapy, increased invasion and metastasis.).

Today as expected there is a session on the DNA damage response, another hot area of research in TNBC biology, and we will be also hearing about progress with CDK4/6 inhibitors in ER+ disease, now that there are at least 2 good agents available (Pfizer’s Palbociclib and Novartis’s  LEE011).

Other than TNBC biology, looking forward to hearing the updates on the big multi-center adaptively-designed I-SPY2 study. I-SPY2 is a neoadjuvant trial looking at whether adding novel drugs to standard chemotherapy improves outcomes, and hopefully how specific biomarkers correlate or not with responsiveness to these agents.  And finally, there is an adoptive T-cell session – an area of intense interest after the recent promising results in other tumor types. Hopefully we can figure out how to make breast cancer cells as susceptible to the immune system as other cancers.

So that’s what’s up folks! More later.

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Mesothelioma Awareness Day

Howdy everyone. Long time no posts huh? Well I have 2 for you now. Earlier this week I did a guest post on TNBC biology and clinical trials for the IBC Network, a local non-profit organization I volunteer with. Check it out here if you are interested! And now…

~ ~ ~ ~ ~

If I said mesothelioma, what would that bring to mind? If you’re lucky you might associate it with asbestos exposure from seeing lawyer commercials on TV aimed at mesothelioma patients who beat the odds.

A couple of weeks ago, I received an email from  Cameron, a caregiver of a woman with mesothelioma, letting me know that today, September 26th is Mesothelioma Awareness Day. His request was for a post about mesothelioma, as his goal was to have 7200 voices talking about disease, to represent the 7200 hours that an average mesothelioma patient has to live. As all all-round cancer geek, how could I say no?

Top 10 facts about mesothelioma as per ME!!!

1) Unlike most cancers (that are more multi-factorial), mesothelioma is almost entirely preventable.

Figure 1: Different types of asbestos fibers - all carcinogenic!

Figure 1: Different types of asbestos fibers – all carcinogenic
(Image from

That is because exposure to asbestos from either occupational sources or at home, is the strongest known risk factor that is avoidable. Indeed 70-80% of cases are linked to asbestos, but only <5% of exposed individuals develop mesothelioma. What does asbestos look like ? See figure 1 for different types. How are people exposed to it? The CDC has some useful information.

2) While the pathophysiology of asbestos as a carcinogen is not fully known due to the long latency between exposure and tumor formation, the overall hypothesis today is that asbestos fibers trigger a vicious cycle of chronic injury and inflammation, which promotes recruitment of macrophages and neutrophils, that generate ROS (reactive oxygen species) and RNS (reactive nitrogen species) inducing  epithelial cell proliferation.

3) Mesotheliomas are epithelial tumors that derive from the mesothelium, or lining of various body cavities. 80% are from the pleural cavity though.

4) One genetic predisposition factor is inheritance of a germline mutation in BAP1 (BRCA1-associated protein), which is a histone modifying enzyme among other functions.

5) Nowadays mesothelioma can be diagnosed via serum-based assay called Mesomark which measures a soluble mesothelin-related peptide that is overexpressed in mesothelioma. More information on this can be found in a recent blog post by Dr Jack West, a thoracic oncologist from Seattle.

6) The average overall survival is only 10 months! Pretty dismal 😦

7) Incidence is predicted to increase by 5-10% each year in most industrialized countries until about 2020. However it is interesting that although the rates in men have been steadily increasing, the incidence in females has remained steady. Did I mention Asbestos is still not banned!

8) Why is the prognosis so bad? Unfortunately, mesothelioma is usually fairly chemoresistant. In patients who are unresectable, however the only form of therapy which is even transiently effective is cytotoxic chemotherapy with Cisplatin and/or Pemetrexed. Even in early stage patients who get surgery first, it is rarely definitive and chemotherapy is used as a “mop-up” strategy. Someitmes, depending on site and degree of spread radiation may be used, although pleural disease is hard to irradiate without harming the lungs.

9) At a molecular level it is rather strange – most tumors have intact Rb and p53 pathways, two key tumor suppressor genes very commonly mutated in cancer. In addition, unlike tumors derived from surrounding visceral tissues (such as lung and pancreas) which often harbor Kras mutation, none of the Ras oncogenes are frequently mutated in mesothelioma. A comprehensive description of the genomics of mesothelioma has not been done.

10) There are no proven targeted therapies. Some areas under investigation include HDAC inhibitors, EGFR inhibitors, and just a few weeks ago, a trial of a FAK inhibitor, defactinib, which targets cancer stem cells was announced by Verastem.


Hope this was educational. If you would like to read more, I recommend visiting Cameron’s site .

If you are feeling charitable and want to donate towards research given the current terrible research funding scenario in the US (see figure 2 below), he recommends the Mesothelioma Applied Research Foundation who are also advocating today on Capital Hill for the cause.

Figure 2: Depressing graph showing a 5% decrease in Science R&D spending in the US, in contrast to China for example!

Figure 2: Depressing graph showing a 5% decrease in Science R&D spending in the US, in contrast to China for example!


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Emotional investment in cancer research – how much is necessary for good research?

One of the thought-provoking articles that has come up repeatedly in my twitter feed this week, is an article in the NY Times about (and written by) a young woman who found out that she carries a BRCA1 mutation. After discussing the reasons behind wanting to know whether she carried the gene mutation, she mentions enrolling in a cancer biology class taught by a

“professor [who] filled his slides with dark oncological puns, lecturing with the almost robotic detachment I sometimes see in those who work closely with cancer”…

Reading this paragraph as a cancer researcher, I asked myself to what extent do I portray the robotic detachment she mentions, and does this lead to better research?  Its now a few days after I read the article but I don’t think I really have an answer yet.

To elaborate, my work now is really translational – if you ask me what the measure(s) of my success over the next few years is, here’s my answer: I would have designed a biomarker-driven treatment strategy for IBC patients that still appears promising after rigorous preclinical work including animal model testing and a clear understanding of mechanism. My data so far on my main project is coming along very nicely!

In addition, because I am in the TRIUMPH postdoctoral training program, I have the unique opportunity to be exposed to clinical issues at a deeper level than virtually any other PhD-track program in the country.  This year, in parallel with my lab research, I am engaging in rotations with various specialties within MDACC (pediatrics, medical oncology, radiation therapy, phase 1 trials, surgical oncology). In reflecting on my experiences so far, and talking with my peers, it is crystal clear to us why we are here.  Papers in nice high-IF journals, awards, invited talks etc are nice (and desirable qualifications for those of us who want to stay in academia), but at the end of the program, many of our goals include being able to see our work translate directly into patient care.

On top of these IRL opportunities, I have enjoyed interacting with a group of cancer survivors and patient advocates on social media and reading blogs, which has given me a deeper understanding of the impact of cancer on people’s lives than the average lab scientist, and made me even more driven to do clinically-relevant work. Time will tell whether time invested in such activities above and beyond my long days in lab, will actually make me a better researcher – but I have my suspicions it will.

In contrast, when thinking back to my PhD which was in a much more basic science-driven department, my success was measured by how elegantly I could prove a mechanism for some biological process (in my case how oxidative stress and DNA damage signals to particular pathways to regulate cell survival/death), and by most people’s definition, I was successful in this endeavor. Looking back at some of my peers I have to admit that I saw some of the “robotic detachment” mentioned in the article, not only from those who worked in cell lines/yeast on fundamental biology questions (like understanding all the binding partners of protein X or what genes ABC transcription factor regulates). Perhaps it was just such fundamental (and SLOW!) research combined with the struggles of grad school that made even the brightest students to sometimes appear uninspired.  However, even some of my colleagues who worked on mouse models of XYZ cancer seemed to care only enough to do their project to their committee’s satisfaction.  To be fair, some superficial level of detachment is probably necessary for working with animals that have to be sacrificed during/after the study, especially after the researcher induced disease (in the most humane way possible).  However deep down, I think that most cancer researchers aren’t very detached from their work. After all, cancer touches us all at some point whether individually or people close to us.  heart-robotMaybe its just a question of degree instead of a black-and-white detached or not attitude. Hey, maybe we can be robots WITH hearts – if that’s what it takes to make a real difference!


What do you think fellow biomedical researchers? Do you feel detached from your work i.e. is it mainly just a fun/interesting way to make a living or are you deeply invested in the broader implications of your work?  Or is the reality of the disease you are working on so depressing that you need some objectivity to survive.


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SABCS mini-series post 2: What’s new and upcoming in triple negative breast cancer?

In this second overview of research presented at SABCS, I thought I would focus on the excitement building with regard to options in triple negative breast cancer (that is tumors that don’t express the estrogen receptor, progesterone receptor or HER2).

In the past, triple negative disease has been defined in terms of what proteins are NOT expressed, but at this meeting, we heard from Dr Jennifer Pietenpol how TNBC is actually a heterogenous disease with 7 subtypes based on a large scale gene expression analysis of more than 3000 tumors from 21 worldwide data sets (not a trivial bioinformatics effort!).  The major take home talk from her fabulous talk is that most of these subtypes have particular targets that may be feasible for targeting. As an example, about 11% of TNBCs actually express the Androgen Receptor (called the Luminal Androgen Receptor subtype), which is known to be a key growth regulator in prostate cancer, but until now has not received much attention in other tumors.  The availability of AR antagonists such as bicalutamide means that now it is possible to target AR in breast cancers as well, although more detailed characterization of its function in breast cancer is still needed.  As such, there will shortly be a trial available at Vanderbilt, using bicalutamide in combination with a PI3K inhibitor (because this subtype is highly enriched for PIK3Ca mutations – in TCGA dataset 50% of the LAR subtype had PIK3Ca mutations vs 3% in TNBCs as a whole).  In case you are interested in reading more, the majority of Dr Pietenpol’s data was recently published in the Journal of Clinical Investigation (Lehmann et al, see references below).

Another interesting talk in the TNBC session on Tuesday was by Trey Westbrook, a young professor at Baylor College of Medicine. His research is focused on using genetic screens to uncover new targets. This functional approach is complementary to many of the large scale genomic screens such as the TCGA and ICGC that are being performed since targets that inhibit tumorigenesis that overlap with gene-level changes (amplification/mutation) are more likely to be true drivers vs passenger changes. In addition, targets that are validated functionally allow us to narrow down a large number of potential molecules for further study, since drug development and even basic research to understand mechanism is quite expensive.

So with that background, I will describe some of Dr Westbrook’s findings from his basic screen using a shRNA library transfected into normal mammary cells that have been immortalized with telomerase and SV40.  The goal was to figure out which shRNAs induce transformation of these immortalized cells, which is tested using a standard anchorage-independent growth assay.  A total of 42 new tumor suppressors were uncovered in this screen, but he only presented data regarding one of them,  that is PTPN12.  PTPN12 is a phosphatase that is mutated in about 5% of TNBCs but when analyzed further is found to be down-regulated by other (unknown) mechanisms in about 60% of TNBC tumors. Next the lab asked what does PTPN12 do? Phosphatases act in opposition to kinases that add phosphate groups to other proteins ie they remove these phosphates, which usually (but not always) turns off a protein.

Figure 1: Network of proteins regulated by PTPN12

Figure 1: Network of proteins regulated by PTPN12

To figure out which proteins PTPN12 acts on, they did an elegant proteomic experiment using SILAC and compared the phospho-tyrosine proteome in cells with high PTPN12 levels and shRNA-depleted cells. What they found was that PTPN12 regulates a whole network of tyrosine kinase receptors including EGFR, HER2 and PDGFb, and that collectively these pathways drive tumorigenesis (see figure 1). This is exciting because there are currently available drugs against many of these pathways, so there is renewed enthusiasm in testing novel combinations of TKIs in this biomarker-defined subset (that is PTPN12 low). As a proof of principle preclinical study in xenograft tumors in mice, a combination of crizotinib and sunitinib to target cMet and PDGFRb (respectively) was tested. Individually each agent showed only very minimal tumor growth delay, however in combination tumor growth was halted, and the mice lived statistically longer (see key tumor growth rate in figure 2).

Figure 2: Tumor growth rate in mice treated with crizotinib and/or sunitinib

Figure 2: Tumor growth rate in mice treated with crizotinib and/or sunitinib

Once again, some of this work has been published recently in Cell, although this specific pharmacological combination was not presented in the publication (Sun T et al, see references)


Lehmann B et al, “Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies” JCI 2011

Sun T et al, “Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase” Cell 2011


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SABCS Mini-series post 1: Pfizer CDK4/6 inhibitor is a #win

I just returned from my first San Antonio Breast Cancer Symposium which was an information-packed week of talks, posters, and meeting interesting people.  I had a blast, learned a ton, and made a valuable connection at a company for a future study.  The next few posts on my blog are going to cover the biggest news items as well as what I personally found the most interesting at the meeting.  But outside of these topics, if you have any questions, feel free to comment and maybe I’ll add a post or just get back to you on it. The online resources available to the attendees of the meeting are vast so even if I didn’t attend that session, I should be able to get an answer for you from them or my twitter colleagues who attended.

I will kick off this short series of posts, with what I thought was the most promising new therapeutic advance, and this is the latest analysis of the trial of Pfizer’s CDK4/6 inhibitor, PD-0332991.   When I was reading up on drugs for the book chapter I just wrote on cell cycle targeted therapies, apart from my own drug of interest, I was most excited about this compound.  And indeed, the clinical results of a randomized phase 1/2 study presented by Richard Finn were stunning! The progression-free survival curve presented is shown in figure 1. “LET” stands for letrozole, a non-steroidal aromatase inhibitor, an FDA approved drug that is currently used in post-menopausal patients with hormone-sensitive tumors.

Progression-free survival curves for PD-0332991

Figure 1: Progression-free survival curves for letrozole vs PD+letrozole in postmenopausal ER+ patients.

To elaborate on this study, which was a worldwide multi-center trial of postmenopausal ER+, HER2- patients based on the preclinical work that highlighted that targeting CDK4/6 only works in the context of cells with intact G1 checkpoint (ie wild-type Rb). In case you are not familiar with the cell cycle, figure 2 has a schematic of the cell cycle and proteins involved in each phase.

Cell cycle schematic

Figure 2: Cell cycle schematic

Note that CDK4 and CDK6, targets of this drug,  function in complex with cyclin D1 to phosphorylate and inactivate Rb, which is a major cellular brake on cell proliferation. It would make sense then that targeting CDK4/6 in the context of tumors cells that have lost Rb would be ineffective. Since luminal (ER positive) breast cancers also frequently overexpress cyclin D1, Pfizer decided to focus on these patients, however they do have an additional 3 separate trials in lymphoma and myeloma, based on preclinical data in these models too.

This drug was incredibly well tolerated, with the majority of the AEs being grades 1 or 2. The only added toxicity over letrozole alone that was observed in more than a few patients was neutropenia, which was described by Dr Finn as “uncomplicated”, and expected for this class of compounds which do affect normal cells as well.

The results of the biomarker analysis was intruiging however for the basic scientists among us. Even though it was thought that cyclin D1 amplification or loss of p16 (which is a negative regulator of CDK4/6 activity) would be predictive biomarkers of sensitivity, and were used to enrich the phase 2 part of this trial for potential responders (after phase 1 found the maximum tolerated dose). However, upon biomarker analysis at the end of the study, they found that these proteins were no better than ER alone at predicting response.  Clearly, further work is necessary to find a biomarker of response (and/or resistance), even though the clinical benefit rate of 70% seen in this study was quite impressive. In conclusion though, based on these data (both preclinical and this study), a registration study is planned to start in 2013.

References (journal articles):

Preclinical breast cancer papers:

“PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro.” – Breast Cancer Res Treatment 2009, pubmed link

“Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors.” – Cell cycle 2012, pubmed link

Preclinical other tumors:

“A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6.” – Cancer Res 2006, pubmed link

“Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia.” – Blood 2007, pubmed link

“Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.” – Cancer Res 2010, pubmed link

“Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma” – Blood 2012, pubmed link


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PARP inhibitors and PI3K inhibitors – a new option in triple negative breast cancer?

This week’s Cancer Discovery had 2 exciting articles on combining PI3K inhibitors with PARP inhibitors in breast cancer. I was particularly intrigued as these papers have a solid mechanistic explanation of the mechanism of synergy so I thought I would do a post on the 2 papers. But first a little background…

PARP enzymes play important roles in a specific type of DNA repair pathway called BER (or base excision repair). PARP inhibitors have been developed to inhibit DNA repair in tumor cells that have other defects in DNA repair, such as BRCA1 or BRCA2

Figure 1: Synthetic lethality in the setting of BRCA1/2 mutation (From: Polyak K, Nature Med 2011)

mutant breast and ovarian cancers (which have defective homologous recombination).  This concept is what is known as a synthetic lethal relationship (see figure 1 for schematic) – either defect alone doesn’t have much effect, but when combined together do have an effect (ie cell killing).  Several PARP inhibitors have been developed, including olaparib and MK-4827, which have been tested in patients with BRCA1/2 mutations.  The results from these trials have been somewhat promising, with response rates between 30-40% without considerable toxicity. However these responses have not been very durable.

BRCA1 and BRCA2 germline mutations only account for 5-10% of all breast cancers however, so researchers have been trying to figure out whether PARP inhibitors might have some utility in patients who have not inherited these alleles.  This is where these new papers come in.

So why the excitement about combination with PI3K inhibition? There are 2 reasons:

* Combinations of PARP inhibitors and cytotoxic chemotherapy is effective in preclinical studies, however in patients unfortunately the toxicities are also additive, especially immunosuppression, which leads to dose reductions/delays. These results suggest that the therapeutic window for these treatment strategies may actually be pretty narrow.

* We already know that the PI3K pathway is highly relevant in most breast cancers in different contexts –as primary genetic defects or as resistance mechanisms to endocrine/HER2-targeted therapy. Specifically in triple negative breast cancer for example, alterations include PTEN mutations, INPP4B phosphatase loss and PIK3CA activating mutations (rarer). Unfortunately despite expressing these potential biomarkers of sensitivity to PI3K inhibition, cancer cells are really smart, and if we just use PI3K inhibitors alone, feedback loops are quickly turned on to help cells survive, so combinations with PI3K inhibitors are definitely going to be the way forward.  In addition, it is known that BRCA1-mutant breast tumors have elevated PI3K pathway activity.

To briefly summarize the 2 papers, starting with my favorite of the 2:

“Ibrahim et al, “PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition” was interesting because the premise of the whole paper is that regular triple negative breast cancers could be made more like BRCA-mutant breast cancers via PI3K inhibition. This is called “BRCAness” and is actually a pretty neat concept, since there is data showing that among triple negative tumors, those with BRCA1/2 mutations actually respond to chemotherapy better.  So why would PI3K inhibition cause “BRCAness”?  It has been known already that PI3K can regulate steady state levels of homologous recombination, so the authors took one of my favorite cell lines MDA-MB-468 which has wild-type BRCA, and knocked down either BRCA 1 or PIK3CA (the catalytic subunit of PI3K), and observed an increase in cells with gamma H2AX, a marker of DNA damage. This phenomenon was also seen with the pan PI3K inhibitor NVP-BKM120. They went on to explore the mechanism further, and showed that PI3K inhibition decreased BRCA1/2 protein level both in cell lines and in 2 out of 3 xenograft models taken from patients which correlated with response to PARP inhibitor treatment. And finally they carefully dissected out the mechanism by PI3K inhibitors decreased BRCA expression, and found the pathway to be via ERK activation of ETS1 transcription factor. The overall model they proposed is in figure 2.

Figure 2: Model for synergistic activity (From: Rehman FL et al, Cancer Discovery 2012 “In the Spotlight”)

The second study: “Juvekar et al, “Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer” basically showed that in a transgenic mouse model of BRCA1-hereditary breast cancer, that both olaparib (the PARP inhibitor) and the PI3K inhibitor NVP-BKM120 could inhibit tumor growth by some degree alone, but when given together caused a 14-fold delay in tumor growth. The growth curves are pretty impressive given that these tumors grow exceedingly rapidly! Tumor growth inhibition by Pi3K inhibition involves many pathways, and they show specifically inhibition of AKT as a pharmacodynamic marker, as well as decreases FDG-uptake as a functional readout. Angiogenesis (growth of new blood vessels) is also significantly decreased by BKM120 treatment.

The mechanism of synergy that they go on to explore involves PI3K inhibition blocking DNA repair via impaired Rad51 recruitment to DNA damage combined with the already existing defect in homologous recombination repair. As a result the tumor cells would become more dependent on PARP-mediated repair, so if you then add a PARP inhibitor, you kill them better. However if the tumors relapsed, these markers of DNA damage were increased over baseline and MAPK signaling could compensate for PI3K survival signals.

In closing, here are a few take-home points I took from both studies together

* Based on the mechanism of action, I would postulate that combining ERK inhibitors in triple negative breast cancer with PI3K inhibitors and PARP would be counterproductive.

* Method-wise, I liked that both studies used patient-derived xenograft models which are now being viewed as superior models to traditional cell-line derived xenografts.  The fact that the Juvekar study saw greater synergy in vivo versus in cell lines, points to why doing such studies in animals is important and may lead to greater insight into mechanisms of action that are not cancer cell-intrinsic.

* Trials with PARP inhibitors and PI3K inhibitors should now routinely be adding gamma H2AX as a pharmacodynamic marker to show that the drugs are working.

References (both free! 🙂 )

Ibrahim et al paper:

Juvekar et al paper:


Filed under Biology/science, Cancer research

How cheap do they think postdocs are?

I am in the lab really late tonight, and finished everything except waiting on my MTTs to be done, so I was just doing some website searching for a few products I need for my upcoming experiments, and I came across an interesting marketing spiel.

During my PhD when I needed a lot of rapamycin for my animal studies, I found this company called LC Labs, as a result of having to shop around, and overall I think they’re pretty cool – they don’t waste money on extravagant  marketing/trade shows/brightly colored catalogs/sales reps etc to keep prices low.  When I figured out how much rapamycin I would need for even the first 2 months of the study (and I had hoped it would last even longer if the mTOR pathway was important!), it would be $40K.  Yikes!   Even though my lab in grad school was very well-funded and we never worried about money, this figure was a bit shocking, so my PI asked us to look around….LC Labs to the rescue….just as an idea 1mg at Sigma is around $279, whereas LC Labs equally pure product is $225 for 500mg!….They have a handy-dandy chart on every product page with their competitors prices based on mass and purity claim which I like again, as it demonstrates transparency.

So even now I continue to check them out for drugs/reagents that I can’t just get for free from the pharmacy here.  On the staurosporine page tonight I read this funny statement that caught my eye:

“Buy 100-300 mg from LC Labs; support a postdoc for 1-2 years with the money you save!”

LOL, but really???  Lets see, if I needed a boatload of it (since it [staurosporine] inhibits many kinases at very low nanomolar doses) and wanted to order 300mg it would cost $1590 from LC Labs.  Most of their competitors don’t sell such a large size, but biorbyt does, and they charge $2245 for the same 300mg (according to the price table)….a $655 difference. Where can I find a postdoc for $655/year or even $655/month? (I’m taking notes for my future lab 😉

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Collaboration in Science Twitter Chat Tomorrow

As the complexity of performing science increases, collaboration is becoming increasingly necessary to accomplish great things.  Collaboration may occur across disciplines, continents and type of environments, but regardless of scope, there are a number of challenges and opportunities in moving forward in this new era of collaborative science especially for young scientists lacking broad networks and experience working with diverse groups of people.

Here at MD Anderson* we’re paving the way for novel types of interactions to become mainstream – who would’ve thought multiple competing pharmaceutical companies each with drugs that would work best in combination, would work together on a clinical trial. Its happening here because we have the power!!! (ie the patients, experience and the leadership)

Other examples of new types of collaborations can include company sponsorship of academic lab activities such as preclinical studies or method validation.

Tomorrow (Wed Feb 1) on the life science twitter chat, which you can participate in by following the hashtag #ls_chat, that my friend @Comprendia and I started last year, we will be discussing collaboration in science.  Some of the topics that we will be discussing include finding opportunities for academic-corporate research collaboration, determining how to make them worthwhile to both parties, and most importantly best practices for being a successful team player in such endeavors.


Please join us tomorrow from 10-11am PT (noon CT/1pm ET) for this (hopefully!) useful discussion between academic scientists, industry scientists and others who are interested in discussing this.  See you on the twitterz!

* note: I’m not speaking on behalf of my employer, just commenting on what’s happening here relating to the content of this post

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Filed under Biology/science, Cancer research