possible progress in prevention of brain mets w mTor inhibitor & MEK inhibitor combo!

[Lani]

not done in people yet and done w triple negative vs. her2+ bc so far, but principle seems sound since mTor inhibitor which has previously been shown to be helpful in her2+ bc crosses the blood-brain barrier

Breast Cancer Res Treat. 2011 Mar 11. [Epub ahead of print]
The effect of mTOR inhibition alone or combined with MEK inhibitors on brain metastasis: an in vivo analysis in triple-negative breast cancer models.
Zhao H, Cui K, Nie F, Wang L, Brandl MB, Jin G, Li F, Mao Y, Xue Z, Rodriguez A, Chang J, Wong ST.

Departments of Radiology and Pathology, Medical Systems Biology Laboratory, Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Medical College, Cornell University, 6670 Bertner Avenue, R6-211, Houston, TX, 77030, USA.
Abstract
mTOR inhibitor rapamycin and its analogs are lipophilic, demonstrate blood-brain barrier penetration, and have shown promising antitumor effects in several types of refractory tumors. We thus try to explore the therapeutic effects of mTOR inhibitors on brain metastasis models. We examined the effects of different dose of mTOR inhibitors (rapamycin, Temsirolimus-CCI-779) on cell invasion in two brain metastatic breast cancer cell lines (MDA-MB231-BR and CN34-BrM2). Antibody microarray and immunoblotting were applied to detect signaling pathways underlying the dose differential drug effects. The in vivo effects of single drug (CCI-779), and drug combination of CCI-779 with SL327 (a brain penetrant MEK inhibitor) to eliminate the unfavorable activation of MAPK pathway were evaluated in MDA-MB231-BR brain metastases xenograft mice. The two mTOR inhibitors, rapamycin and CCI-779, inhibited the invasion of brain metastatic cells only at a moderate concentration level, which was lost at higher concentrations secondary to activation of the MAPK signaling pathway. Pharmacological inhibition of ERK1/2 by PD98059 and SL327 restored the anti-invasion effects of mTOR inhibition in vitro. In vivo, a significant decrease was noted in the average number of micro and large metastatic lesions as well as the whole brain GFP expression in the CCI-779 1 mg/kg/day treated group compared with that in the vehicle group (P < 0.05). However, 10 mg/kg CCI-779 treatment did not show significant anti-metastasis effect on the animal model. High-dose CCI-779 eliciting the ERK MAPK activation in the brain metastatic lesion was corroborated. Combined with the brain penetrant MEK inhibitor SL327, high-dose CCI-779 significantly reduces the brain metastasis, and the combination treatment prohibited perivascular invasion of tumor cells and inhibits tumor angiogenesis in vivo. This study provides evidence on the potential value of CCI-779 as well as CCI-779 + SL327 in prohibiting breast cancer brain metastasis.

PMID: 21394501

[gdpawel]

Some cell-based assay labs have explored the biology of PARP inhibitors, alone and in combination, in actual human tumor primary culture micro-speheroids, in breast cancer. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

To date, one lab has observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients. Work is ongoing with these BRCA1 positive patients as wells as other tumor types where the PARP inhibitors may prove useful in the future. The PARP inhibitors are turning out to be very useful.

On April 3rd, Dr. Robert Nagourney will have a Poster Session at an American Association for Cancer Research (AACR) on the most recent findings on novel compounds that target two parallel pathways in cancer cells. These small molecules, Olaparib (AZD2281) and Iniparib (BSI-201), disrupt the signal that drives cancer cell survival and proliferation (cell growth).

Cell function analysis of the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture micro-spheroids: Exploration of horizontal pathway targeting. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still.

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When clinical therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies.

This is what has been observed with these duel inhibitor combinations.

What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear.

Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of cell-based functional profiling platform. It allows the exploration of drugs and combinations that most oncologists wouldn’t think of.

It is these counterintuitive explorations that will likely lead to meaningful advances.

Functional profiling measures biological signals rather than DNA indicators, which plays an important role in cancer drug selection and is demonstrably greater and more compelling data currently generated from DNA analyses.

The results of their investigation support the clinical relevance of targeting the MEK/ERK and PI3K/mTOR pathways and more importantly, suggest "dual" pathway inhibition (horizontal) to be a productive strategy for further clinical development. Disease specific profiles and sequence dependence are being explored and will be reported.

Most solid tumors reveal complex interactions between signal pathways that cross talk at points of commonality. To examine the clinical potential of BEZ235 and AZD6244 - inhibitors of PI3K and MEK/ERK pathways - they applied cell function analysis of programmed cell death to tumor micro-spheroids (microclusters) isolated from 24 patients. Drugs were tested alone and in combination.

According to researcher, Professor Alan Ashworth, director of the Breaktrhough Breast Cancer Research Centre in London, the BRCA1 and BRCA2 genes are involved in a repair pathway for double-strand DNA breaks that occur very close to each other. An elaborate mechanism called homologous recombination fixes some of these double-strand breaks, and BRCA2 and BRCA1 are critical for homologous recombination.

PARP is a very active enzyme involved in the repair of single-strand breaks in DNA or modified bases. It binds to DNA damage and adds multiple sugar molecules to the DNA that act as a beacon to recruit other components of DNA repair.

Emerging work on assays (PARP levels correlating with response to PARP inhibitors) have shown pretty good response with PARP inhibitors as single agents in BRCA1 positive patients and in some triple negative patients. There has been some results combining the PARP inhbitors with mustard alkylators, platins and drug combinations to optimize PARP inhibitor combinations.

Robert A. Nagourney, Paula Bernard, Federico Francisco, Ryan Wexler, Steve Evans, Rational Therapeutics, Long Beach, CA. Proceedings of AACR - Volume 52 - April 2011.

[gdpawel]

The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the AACR 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with expectations. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that his lab blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This has interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in the report was, perhaps, its most important. Specifically, that the lab can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When they combined both pathway inhibitors in a process called horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Rational Therapeutics, Inc.

[radiant]

gdpawel:


>>These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.<<
---------------
This sounds very encouraging, but how can they do this? I"m gleaning from your post that you are saying cancer researchers, and specifically folks at Rational Therapeutics, are discovering specific targets to go after to stop cancer from spreading. And, now they can test ways to supress these cancer targets this w/out having to go through a clinical trial process? That's amazing.
I'm guessing what you are saying is now they can perform more research in the lab, instead of having to do beginning research at this level on cancer patients in clinical trials? Is that what you are saying.
I'm not good at understanding the detailed clinical language.
Thanks for your help!
Kim

[gdpawel]

Kim

The lab actually tests "your" tumor cells against the drug agents (in this case, PARP inhibitors). How do "your" cancer cells (not population studies) respond in the presence of various drug agents. Do they die or not? They measure the net effect of all the processes going on within the cancer, acting with and against each other in "real-time" (prospectively) and test living (fresh) cells (not dead cells) actually exposed to the drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed, regardless of the mechanism. Both genomics and proteomics may identify potential therapeutic targets (that's good), but these targets still require the determination of cellular endpoints (point of termination) in "drug selection."

Greg

[radiant]

Wow. How would a patient get involved in something like this? Wait - I think I know. The patient sends a live sample of their tumor down and then it gets tested?

- Kim

[gdpawel]

Kim

And there is very good reasons for testing a live sample of a patient's tumor (3D analysis). Cancer is already in 3D conformation. When you profile cultures "fresh" live in 3D conformation, it measures the function of cancer cells (is the whole cell being killed regardless of the targeted mechanism or pathway). Real life 3D analysis makes functional profiling indicative of what will happen in the body. It tests cells in their three-dimensional (3D), floating clusters (in their natural state - not dead cells).

Researchers at Johns Hopkins and Washington University at St. Louis have recently found out, our body is 3D, not 2D in form, undoubtedly, this novel step better replicates that of the human body. Traditionally, in-vitro (in lab) cell-lines have been studied in two-dimensions (2D) which has inherent limitations in applicability to real life 3D in-vivo (in body) states. Recently, other researchers have pointed to the limitations of 2D cell line study and chemotherapy to more correctly reflect the human body.

And other recent studies have shown that three-dimensional (3D) tissue culture models have an invaluable role in tumor biology, providing some very important insights into cancer biology. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization, they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model.

Due to their enormous potential 3D tumor cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumor models.

Greg

[hutchibk]

So, how does this work if there is no tumor available? Not all tumors are necessarily excisable. That said, say an early tumor was excisable and later metastatic tumors weren't. As I understand it, not always are all tumors equal. My initial tumor and my first recurrance tumor (the only two that we have samples of) have some similar pathologies, some differing pathologies. There are possibilities that further metastatic tumors that we don't have/can't get samples of, will also have some differing pathologies. I also understand that many treatments (which are changed regularly and often as metastatic patients recur) can change the pathology and nature of subsequent tumors.

Just wondering how all this plays out, when a 'fresh live tumor cell' might not be a possibility?

[gdpawel]

Brenda

The surgical specimen is the "personalized" part of personlized cancer medicine. The tissue, carefully excised by the surgeon and analyzed by the pathologist is the source of crucial information that informs the decisions and actions of medical oncologists. Surgeons and pathologists are the custodians of the specimens and therefore the molecules that represent the personalized part of personalized cancer medicine. As the custodians of the tissue, they will also be central to improving cancer management. Aggressive surgery is the best option for early and advanced-stage cancer patients.

Without personalizing cancer medicine with a surgical specimen, there is the traditional trial-and-error protocols that oncologists have been using for years. Or, if you are okay with just a refinement of statistical data, there are DNA and RNA-type tests based on population research (not individuals) that base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. Cancer medicine based on "odds" that you are just like the median in some population of patients tested in a clinical trial. However, the chance that you are that median patient is actually quite small.

You are correct, genomic instability is the hallmark of cancer. The mutagenic (changes in form) effects of the wrong (ineffective) chemotherapy on a genetically-unstable tumor can drive the tumor into a state of more aggressive behavior. You might kill off a whole lot of cancer, only to cause a mutation in the remaining cancer, such that the remaining cancer behaves in a more aggressive fashion.

There is really no right mutation or wrong mutation. There are the right drugs and the wrong drugs. There are "sensitive" drugs and there are "resistant" drugs. Patients would certainly have a better chance of success had their cancer been "chemo-sensitive" rather than "chemo-resistant" where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.

Greg

[hutchibk]

Of course, personalization of treatment is optimum, but not always possible by this method... just wanted folks to understand the caveats.

My oncs (and I have 4 of them) don't necessarily agree with the thought that aggressive surgery is always a good idea for advanced stage cancer patients with metastasis. (or early cancer in a difficult location). For one thing, if an advanced stage cancer patient has multiple tumor sites, perhaps not all of them are operable. As well, if they were, and the pathologies showed up different in different tumors, it could prove very complex/virtually impossible to determine which would be the optimum systemic treatment, which then again becomes a "trial and error protocol." There are a whole host of complications and risks that come with surgeries, especially complex surgeries that might be considered by most to be inoperable, no matter how carefully excised. For instance, the tumor that was on my infindibulm/sella turcica is millimeters from optic nerves and the pituitary gland. It is most definitely inoperable, no matter how precise a surgeon might believe they are. Too many risks. Radiation and systemic treatment is the more controllable choice. And then there is the risk of devastating infection.

[radiant]

ok thanks gdpawel for clarifying this!

- Kim