AACR Advances in Breast Cancer Research San Diego 10/2013

Notes from Susan Love MD

I spent the weekend at the AACR Advances in Breast Cancer Research Meeting in San Diego, where we shared a poster about the Army of Women to try to seduce more scientists to use this resource.  While I did not get to hear all the sessions here are my notes from both the abstracts and the talks.  I hope it gives you both a taste of the meeting and encouragement as to the types of research that are being done.  I was impressed in general with the number of talks focused on metastatic disease as well as the subtypes. 

The opening keynote session was on tumor plasticity and reactive stroma in breast cancer metastases from Yibin Kang at Princeton. The abstract started with “Metastases represents the most devastating stage of cancer progression: The multi-step cascade of cancer metastasis is driven by both intrinsic changes of cancer cell properties, as well as the stromal reaction to tumor cells.” My usual metaphor for this is thinking of a neighborhood where the individuals in the neighborhood with their own talents, neurosis, and problems (the actual cancer cells) interact with each other and also relate to the conditions and other people in the neighborhood i.e. graffiti, garbage on the street, drug pushers, crime, gangs etc.  All the factors combine together to lead to bad things happening.  This keynote was focused on how the original cancer cells change from epithelial cells to mesenchymal cells (called epithelial to mesenchymal transition or EMT) to spread in the blood stream and then once in their chosen tissue change back again.  They have found a new transcription factor that is critical for this process in both directions and may well be able to serve as a suppressor of EMT and therefore of metastases.  It could also potentially put metastatic cells back into a dormant state. This is still in rats but holds promise and would not be a form of chemotherapy but rather a molecular type treatment i.e. more like the hormonal (although it is not a hormone) than chemotherapy.  They also talked about their studies on bone metastases and have identified TGFbeta and Notch signaling pathways as important and that their inhibitors could reduce bone metastases.

There were a number of talks about clonal evolution of cancer cells.  This springs from the acknowledgement that there are different kinds of breast cancer.  The question is whether they all start from the same cells or different cells.  “Metastatic progression is of interest as an evolutionary process, wherein the resulting heterogeneity of primary and metastatic tumor is of interest, as is evidence of drivers unique to one or more metastases.” In other words, cancers evolve over time i.e. if you get a certain treatment you kill the sensitive cells and select for the cells that are not sensitive to it which can then flourish “Both genetic and non-genetic clonal selection occurs in human cancers, explaining variations in tumor composition over time.”  As an aside there is an increasing push for “liquid biopsies” which look for tumor cells in the blood and characterize them.  The technology for this is still in development and we don’t know whether it is really representative but it is coming.

The second session started out with a talk which started saying “There are multiple challenges to developing new therapies to prevent or treat metastasis including our lack of understanding of 1) how disseminated tumor cells remain “dormant” for long periods of time and the processes required for these cells emerge as overt metastases 2) why is established metastases are so resistant to existing therapies and 3) whether there are unique features of established metastases including their microenvironment, that might be exploited for therapy.”  A big problem has been the absence of an animal model.  Now the group at Huntsman Cancer Institute in Salt Lake City has developed patient-derived tumor grafts (also known as patient-derived xenografts or PDX) where they implant tumor cells or fragments from patients into immune deficient mice.   They have a bank and report that chemotherapy sensitivity and resistance in PDX models closely parallels therapeutic response in patients.  They also have found that the Ron receptor tyrosine kinase pathway is a major driver of breast tumor progression and metastasis.  They have shown (in their models) that Ron inhibitors can prevent tumor growth and metastases even in highly chemoresistant models of established MBC.

Lewis from Baylor has identified tumor initiating cells (TIC) or cancer stem cells as being resistant to treatment and is using PXD (see previous paragraph) to screen experimental therapies.

Several other talks were on stem cells and lineage tracing i.e. which cells (correlating to types of bc) come first, second etc.

Another talk was on tumor dormancy and metastasis.  This addresses the fact that some cancer cells get “out” in everyone but many remain dormant wherever they land.  You really don’t care if they are there as long as they are “sleeping” and not causing problems. They actually have a way to directly observe individual cells and have noted that a subpopulation form “migratory streams” and insinuate themselves into blood vessels when associated with macrophages (a kind of white blood cells). The expression pattern of these cells is called the Invasion Signature (they are not very original) and they have identified the Mena pathway as a master regulator of this process.  They have also imaged in real time live tumors where they can see the interaction of tumor cells with macrophages and endothelial cells (cells lining blood vessels) during their invasion of blood vessels and found that the three combine in a particular enabling microenvironment.  They now can identify this and predict prognosis and of course the next step will be figuring out how to block it.

A talk from Germany focused on circulating tumor cells and bone marrow micro metastases.  We now have ways to detect tumor cells in the blood and bone marrow at the single cell level.  Unfortunately we haven’t yet fully figured out what they mean or what to do about them i.e. if they all become dormant do we really need to treat them?  While many of these cells end up in the bone marrow a significant fraction remain over years in a dormant stage and little is known about the conditions required for the persistence of dormancy or the escape from the dormant phase into the active phase of metastasis formation.  As I mentioned above one use for this test might be to see the markers of the metastatic cells can be determined from a “liquid biopsy” i.e. blood test.  Not quite here but coming soon.

Androgen receptors may be more important that estrogen receptors.  Turns out that the androgen receptors are more commonly expressed in breast cancers than estrogen or progesterone receptors.  A group of Canada and Chile (interesting combination) found that some ER positive tumors can switch from growth driven by estrogens to growth driven by adrenal androgens particularly when the estrogen pathways are inhibited by standard hormonal treatments.  “Since approximately 30% of metastatic ER positive tumors exhibit new resistance to standard endocrine therapy and all patients with metastatic disease ultimately progress with acquired resistance, targeting the androgen receptor may be clinically useful.” They have clinical trials on this going on with enzalutamide and bicalutamide which are new androgen receptor blockers.  Interestingly they found that a subset of triple negative tumors expresses androgen receptors and they have been able to show an effect in cell lines.  There also may be some benefit in the Her 2 neu positive but non-amplified types.

There were also talks on PARP inhibitors, and inhibitors of P13K/TOR and mTOR that are in development.

Finally there were my favorite talks on how tumors affect the microenvironment in both primary sites and metastasis.  It really is a community of cells in there and they are all interacting with each other. To quote one of my heroines Zena Werb “While it is now clear that proliferation of tumor cells alone does not cause cancer, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activate stroma certainly potentiates and/or promotes neoplastic risk and leads to metastasis.  In fact, sometimes the trigger for neoplastic progression may come from signals within the stromal microenvironment.  The stromal microenvironment consists of fibroblasts, macrophages, neutrophils, vascular components, nerves and inflammatory cells of the innate and acquired immune response as well as the extracellular matrix that they elaborate along with the molecules that are concentrated and immobilized on it.  All of these components communicate with each other and with the neoplastic cells to contribute to the aberrant tumor organ.”  You also need the right neighborhood for mets to succeed, which is why you don’t see them in every organ but only certain ones.  While this sounds overwhelmingly complicated it really is pretty cool.  It means that using poison to kill the cancer cells is probably a pretty drastic step and we may well be evolving to changing the neighborhood i.e. cleaning up the graffiti and getting rid of the drug pushers and gangs!

The next talk also from San Francisco added yet another element that tumor cells do better in “stiff” tissues.  It made me think this may have something to do with breast density.  Of course breast density is also representative of the neighborhood!

The last talk was a bit above my head but what I got from it was that the next wave of treatments for breast cancer will be immunological either vaccines or drugs which wake up the immune system to kill the cancer cells or at least make the neighborhood less appealing….is that putting more cops on the street?

While much of this may not be impacting your treatments today, it is impressive that many of these theories have led to drugs that are currently in clinical trials.  This is around the corner.

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2 Responses to Comments on AACR Advances in Breast Cancer Research

  1. Vera says:

    Hello!

    I’ve started the petition “President Barack Obama: Fund research on the mouse mammary tumor virus.” and need your help to get it off the ground.

    Will you take 30 seconds to sign it right now? Here’s the link:

    http://www.change.org/petitions/president-barack-obama-fund-research-on-the-mouse-mammary-tumor-virus

    Here’s why it’s important:

    A significant proportion of human breast cancers – 40 percent – contain gene sequences that are very similar to that of a retrovirus that is known to cause breast cancer in mice. The research behind a potential human mammary tumor virus is marching forward steadily, as Drs. Pogo, Etkind, and Melena study the statistical analysis and biochemical pathways of the potential virus.
    A virus works by first replicating in a primary cell and infecting supplementary cells as it grows and divides. Human breast cells divide with the circulating estrogen hormone. When the breast cell with the viral gene sequence divides, it releases viral particles that poison other breast cells and causes a cycle of infection.

    If we can determine that the mouse mammary tumor virus causes as much as 40 percent of breast cancers, we could focus on creating a vaccine to prevent the disease in women. This could lead to a significant gain for The Pure Cure: the primary prevention of breast cancer.
    However, we need further funding to determine whether this virus could potentially cause breast cancer in women. We implore President Obama and his administration to focus their research spending toward the mouse mammary tumor virus. If we can find the causes of breast cancer and potentially create a vaccine to prevent breast cancer, we could save the lives of hundreds of thousands of women around the country.
    Over the last five years, Dr. Kathleen T. Ruddy, breast cancer surgeon and Founder of the Breast Health and Healing Foundation, has focused all her efforts onto moving forward with this research and preventing the disease. The documentary filmmaker Steve Zukerman is currently developing a film about Dr. Ruddy’s efforts and the researchers working on the possibility that a virus may cause breast cancer. The movement toward primary prevention is marching forward. Will you join our cause?

    Thanks!
    Vera Viner

  2. Nicolae says:

    Tumor cells and diseases caused by them, is a complex issue with many unknowns, and this makes the efforts of doctors and patient expectations are often futile.
    All information held current man on tumor cells are practically insufficient to efficiently solve problems of malignancies. To do this, we must first fully expanded horizon of knowledge, the new information is “key” in this area, and I did this with all my passion and strength – in the research study entitled “All about malignant cells and fighting their “And now, the importance of new discoveries for our defense, can be decisive.

    All about combating malignant cells and their
    After a huge effort we made a broad unprecedented work, to show the world explicitly relies basically on the secret, the power and the “famous invincible force” of malignant cells. I made this effort, because man knowingly to can organize better strategy for defense against malignancies. I wanted the world to know, who actually sits behind the emergence and development of malignancies in humans and their mechanisms are selectively vulnerable you can be attacked. And now, looking for support to publish and disseminate these new fundamental information that can lead practically to solve these problems. News from the field, contained in my works can make a revolutionary change in preventive and defensive combat defense against malignancies. I focused all my attention and force to make this original work of research, contained in four books. For a long time people are still waiting to discover something new in this field, which can effectively protect human health and life threatened by this disease dramatically. Impact of new information knowledge about tumor cells in this paper may help in its fight decisive man defense with tumor diseases. Now we have this original work, and unfortunately, one, I able to edit or make known to the world or at least one of these four books, which is most representative of them and entitled “Life Above of anything. “While many people still hope and still waiting for years, something new appears to effectively protect human health and life of this cruel disease, now all this new information with such importance, still hidden among papers and documents My without them to have a chance to edit, to be known, experienced and above all to be for the benefit of man.
    In this regard seek sponsorship to edit one of these works.
    Thank you for your attention and possibly support.

    With esteem and respect the author of this work
    Nicolae Gheorghe
    Loc. Pitesti
    Romania
    Ccnt_nicolae@yahoo.com

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