Tag Archives: cancer

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…

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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 http://amlbenzene.net/diseases-asbestos.html)

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.

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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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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: http://cancerdiscovery.aacrjournals.org/content/2/11/1036.full

Juvekar et al paper: http://cancerdiscovery.aacrjournals.org/content/2/11/1048.full

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Recent Science Roundup 1

Its been a busy few weeks since my defense when I last blogged.  We had a nice trip to DC to receive the Cozzarelli award from the National Academy of Sciences, then the following week I had my folks in town for graduation, and in between, did thesis corrections and paperwork. Yes, they don’t tell you but the paperwork is the worst especially when you have committee members in 3 cities (5 separate buildings)…

Last week was a semi-normal lab week, and now I’m in sunny San Diego for a little break to visit my friend Mary Canady…. So I thought I’d start blogging some real science, so thought I’d try a short-summary format for a few pieces of science that have been mentioned in the media recently, not necessarily in my areas of expertise. Let me know what you think of this format.

1) Coffee consumption decreases risk of ER-negative breast cancer

This is an interesting Swedish epidemiologic study published very recently in the open access journal Breast Cancer Research. The basic design of the study, which attempted to replicate previous studies, is what is called a case-control study, where 2,818 cases (ie patients) and 3,111 controls (non-breast cancer patients, matched as closely as they could) were analyzed.  Importantly, pre-menopausal women and those who had other cancers previously (except non-melanoma skin cancer or in situ cervical cancer) were excluded so these results can only be extrapolated to the post-menopausal setting.  A detailed

Coffee cup with a heart

Mmmm coffee!

questionnaire allowed the correlation of tumor status with coffee consumption, and factors including HRT use, educational level and alcohol consumption also taken in account.  The overall conclusion drawn was that high coffee consumption (defined as 5 cups per day) can modestly decrease the risk of ER-negative breast cancer (which is the more aggressive form that cannot be treated with anti-estrogen therapy).

My training in basic science of cancer biology leads me to postulate on some of the potential mechanisms of this protection, which are briefly proposed in the discussion section.  Coffee is known to contain hundreds of chemicals, including caffeine and polyphenols which have the potential to act both as carcinogens or as chemo-preventive agents, and dissecting out which is responsible for the protection will be a challenge. Caffeine is known to be an inhibitor of the ATM/ATR proteins which I worked on in my PhD which are involved in sensing DNA damage and inducing repair, which would be an undesirable effect of high coffee consumption, however coffee is also the largest source of anti-oxidants in the US diet, and there are weakly estrogenic compounds such as trigonelline in coffee which would only promote the growth of ER-positive breast tumor cells but have no effect on ER-negative cells.

The major downside of this study is that it’s merely a correlation – establishing causation in vivo for something as widely consumed as coffee would be a major challenge. While it’s definitely possible that this negative relationship between coffee consumption and cancer risk is merely a marker of some other factor that is indeed correlated with cancer risk, I tend to doubt this explanation given what is known about the role of coffee in cancer risk in other tumor types as well, and the vast number of chemicals found in coffee that could possibly regulate steps involved in tumorigenesis.

So while this is not medical advice, I think it’s probably safe to say enjoy your coffee in moderation and there may be a potential health benefit in some circumstances.

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OK I had thought of doing multiple articles per roundup (hence the #1 on my subtitle) but it seems maybe one is long enough. What do you think?

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References:

1. Allred KF, Yackley KM, Vanamala J, Allred CD. Trigonelline is a novel phytoestrogen in coffee beans. J Nutr. 2009;139:1833-8.

2. Arab L. Epidemiologic evidence on coffee and cancer. Nutr Cancer. 2010;62:271-83.

3. Ganmaa D, Willett WC, Li TY, Feskanich D, van Dam RM, Lopez-Garcia E, et al. Coffee, tea, caffeine and risk of breast cancer: a 22-year follow-up. Int J Cancer. 2008;122:2071-6.

4. Li J, Seibold P, Chang-Claude J, Flesch-Janys D, Liu J, Czene K, et al. Coffee consumption modifies risk of estrogen-receptor negative breast cancer. Breast Cancer Research. 2011;13:R49.

5. Tang N, Zhou B, Wang B, Yu R. Coffee consumption and risk of breast cancer: a metaanalysis. Am J Obstet Gynecol. 2009;200:290.e1-9.

6. Yu X, Bao Z, Zou J, Dong J. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer. 2011;11:96.

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