ER+ Cancer and drug resistance

Hopeful82014

http://www.cancer.org/research/acsresearchupdates/breastcancer/searching-for-a-solution-for-when-er-positive-breast-cancers-outsmart-treatment#

I stumbled on this today and found it intriguing.

JohnSmith

Changing the PI3K inhibitor dosing schedules is an interesting idea. It sounds like they are grasping at straws to find ways to lower toxicity (side effects).
To quote Miller: "Once the cancer cell is dead, there's nothing else to inhibit."
If this intermittent dosing approach is valid, wouldn't it theoretically apply to virtually all drugs used in cancer therapy?
Also, how do they know if the cell is dead?
There are no tools in existence to identify cell lifecycle in "real-time".

Perhaps the problem with PI3K inhibitors is that numerous other pathways are still "on" and cancer cells recognize that the PI3K pathway is blocked and choose a different pathway to survive. Shutting down two pathways may not be enough.
Think "Combination Therapy". The Combination Therapy model says multiple drugs are needed to block the multiple pathways cancer exploits to survive and proliferate. Doing this without adding significant toxicity is a massive challenge.

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Here's the full article:

October 7, 2015

Most breast cancers depend on the female hormone estrogen to grow and thrive. That's why anti-estrogen drugs like tamoxifen are the cornerstone of therapy for the millions of women with estrogen receptor-positive (ER-positive) breast cancer. While these medications have saved many lives, they don't work for all women. In about a third of patients, the tumors learn to adapt to the estrogen-free environment and hormone therapy stops working.

This form of disease is "virtually incurable with approved therapies," says Todd Miller, PhD, assistant professor of Pharmacology and Toxicology at Geisel School of Medicine at Dartmouth.

Why anti-estrogen resistance occurs is a hot topic of research. In recent years, scientists have learned that a signaling protein, called phosphatidylinositide 3-kinase (PI3K), helps drive breast cancer cell growth.

"It's an alternative pathway that breast cancer cells use to compensate for the lack of estrogen signaling, which occurs when you use medications like tamoxifen," explains Miller.

Turning off that pathway then should, theoretically, help halt breast cancer cell growth. The idea has held such promise that ongoing clinical trials have been testing a combination of anti-estrogen drugs and experimental PI3K inhibitors in women with ER-positive breast cancer. But there's been a glitch.

"The clinical trial results are not terribly impressive, and they really should be," says Miller, who has been awarded an American Cancer Society research grant to investigate the underlying mechanisms of anti-estrogen resistant breast cancer. "So, we decided to look at this in more detail. Instead of just putting two drugs in patients and expecting the tumors to melt away, we asked the question: 'What's actually happening to the biology of the tumors over time when you use these drugs?'"

Nemesis of the Field

Why hasn't the combination of PI3K inhibitors and anti-estrogens worked the way everyone has hoped? Miller believes his findings, in mice and cultured breast cell lines, reveal important clues.

"What you would expect to happen, does happen at first. The tumors melt away and cells start to die really quick," he says. "But then things change over time and the drugs are not doing the same job."

His research suggests that the daily dosing schedules being used in clinical trials may be the culprit. These regimens call for long-term suppression of PI3K. Patients are given escalating dosages of the drugs over time until it becomes too toxic and then the dose is scaled back but never stopped.

"This didn't make a lot of sense to us," Miller says. "With the combination of an anti-estrogen and P13K inhibitors, if we are really trying to [kill the] tumors, we shouldn't need to continuously inhibit the pathway. Once the cancer cell is dead, there's nothing else to inhibit."

Yet, most PI3K inhibitors are designed to do exactly that – continuously shutdown the signaling pathway.

"This is the often unsubstantiated mainstay of the field for almost ten years, that you need to chronically suppress the signaling in order to see anti-tumor effects. But it's just not true," Miller emphasizes. "Drug companies do not need to design their drug to continuously inhibit the pathway."

During the course of his research, Miller's discovered that different P13K dosing schedules result in different patterns of breast cancer cell death and growth. Intermittent, high-dose treatment appears to work better than long-term, lower-dose regimens that only partially switch off the pathway. After testing a weekly schedule in mice, he found it still halts the growth of ER-positive breast cancer cells and causes the tumors to shrink.

"The current treatment schedules in clinical trials call for patients being treated every day, once a day and they accumulate side effects in the process," Miller says. "Our work suggests if you were to treat once a week or once a month, you may not get the same side effects but you would get the equivalent anti-tumor effects."

Some may fear that stopping a PI3K inhibitor, which would turn the pathway to back on, could give cancer cells the chance to start growing again. Miller says that's unlikely.

"When you switch it off for a number of hours or days the cancer cells will die. When you switch it back on, the cancer cells are dead, so now only your normal cells are being reactivated." Allowing your normal cells to "turn back on" can potentially help alleviate side effects.

"In a perfect world you would take this drug for a week and never take it again but that's not reality. The reality is, or what we hope to achieve, is that you would take it for a few days or once a month, and then take a couple of weeks off."

Getting a Drug Company to Listen

Miller's team has submitted a research paper detailing their findings that he hopes to publish soon. The next step, he says, is "to get a drug company to listen to me" and launch a phase 1 clinical trial with a different dosing schedule that could maximize beneficial effects while minimizing toxic ones.

Ultimately, he hopes his findings will help identify when and how to best incorporate P13K inhibitors in the care of women with breast cancer.

"For women with early stage breast cancer, these drugs are too experimental to put into routine use for patients who might be cured with surgery," Miller says. "However, for patients with metastatic ER-positive breast cancer, there is good data to suggest these drugs have the potential to help control the cancer in combinations with anti-estrogens."

Hopeful82014

Spot on, John. Thank you for your insights, which always add a great deal of value to the discussion.

I think this demonstrates just how far we have to go, in terms of actual treatments, understanding of the disease and (perhaps most importantly) in adopting fresh approaches to the research that will move us forward.

BarredOwl

Hi:

If you google "intermittent dosing" you will see it is indeed widely used. Among other factors, whether such regimens are effective likely reflects drug mechanism of action.

The comments in the article about cell death and resumption of growth of the remaining live cells are likely based on pre-clinical studies. A variety of in vitro methods can assess cell death (viability) and even progression through the cell cycle in real time (e.g., with immunofluorescence/flow cytometry on serial samples or even more modern methods).

Google: "cell viability"

Google: "monitoring cell cycle in real time"

BarredOwl

Hopeful82014

Thanks, Barred Owl.

Lojo

I've wondered about this in the context of treating / managing the development of antibiotic resistance among infectious agents - which is an evolutionary process - antibiotics select for resistant cells, so that any bacteria resistant to the drug keep growing, even if they're not otherwise very fit relative to non-resistant cells (which they usually aren't). I know they're developing algorithms for dosing infectious diseases to manage the evolution of antibiotic resistance and I know they're looking at combination therapy/intermittent dosing to manage resistant TB, and I know they have recently been examining cancer cells on an evolutionary model -- and when I began taking tamoxifen, I wondered if a changed dosing schedule would promote or inhibit the development of tamox resistance among any remaining tumor cells. I also wonder why (at least for post-menopausal women) combination therapy with tamox and AI's hasn't been tried as a first line of treatment -- side effect management?

JohnSmith

As BarredOwl said, "intermittent dosing" is tied to the mechanism of action.

I reached out to the researcher quoted to get some clarification. Comparing PI3K inhibitors to Tamoxifen, I asked about the mechanism of action.

He replied essentially saying:
With some drugs (such as PI3K inhibitors, and conventional chemo's), intermittent dosing may work because these drugs are CYTOTOXIC, meaning they are designed to kill cells.
Some drugs have more of a CYTOSTATIC effect; this is how we think anti-estrogens such as tamoxifen work; they just inhibit cancer cell growth/proliferation without killing the cells. So anti-estrogens like tamoxifen need to be dosed continuously (we think).

In terms of cell death:
Correct, we cannot tell if cancer cells are dead (in humans) in real-time. We have animal model data, and we have abundant observational data from humans. For example, patients are treated with certain drugs for 1 year after surgical removal of a tumor from the breast. Different treatment durations have been tested, but the 1-year regimen is as effective as a 2-year regimen at preventing cancer recurrence/metastasis; thus, we infer that the treatment induced cancer cell death within the first year, and the second year had no additional effect; if the treatment only had a cytostatic effect, we would expect that one extra year of treatment would give one extra year of preventing cancer recurrence/metastasis.

In terms of combination therapy:
Combination therapies to block multiple pathways will be most effective. That is why PI3K is important: when estrogen signaling is suppressed with an anti-estrogen, PI3K pathway is activated, so we are co-targeting estrogen pathway and PI3K pathway. Single-agent clinical trials are only used to test new drugs; once proven to be safe, these drugs are almost always tested in combination with other anti-cancer drugs in further clinical trials…. That being said, toxicities due to combination therapies are a real obstacle. We are actually quite good at killing cancer cells, but we also kill normal/healthy cells in the process. The trick is finding a reasonable "therapeutic index/window," which is the different between toxicity (we aim for low) and anti-cancer effect (we aim for high).

Fallleaves

Very interesting information, Johnsmith! Thanks for making contact with the researcher for further clarification, and sharing what he said with us. If he's right, and I hope he is, this could make a lot of cytotoxic treatments more tolerable to patients, and therefore more effective. This study was the first I've learned that P13K signaling is activated by anti-estrogens. P13K inhibition may prolong trastuzumab (Herceptin) effectiveness, as well.

JohnSmith

I read this recent AACR article, here, about combining a PI3K inhibitor (BKM120 or BYL719) with a PARP inhibitor (Olaparib) and thought of this thread.
The NCT01623349 clinical trial, here, is doing this for the TNBC cohort.

Is it feasible to design a similar trial that combines an anti-estrogen, PI3Ki and PARPi for HR+ patients?
Other than toxicity, any reason why this would be a bad idea?

JohnSmith

I think you're right kayb. I wasn't aware of the biomarkers for PARP. The majority of the 20+ trials for Veliparib lean towards ER-, with these exceptions (I haven't gone through them all yet)
www.clinicaltrials.gov/ct2/show/NCT01281150
www.clinicaltrials.gov/ct2/show/NCT01351909

There's also these PARP inhibitors (Niraparib, Olaparib, Rucaparib, Talazoparib, etc) which I have not searched on clinicaltrials.gov.
There may be more. I'll do some more digging and edit this post later.

I did see this news published January 18, 2016: "Approved for ovarian cancer patients that have BRCA mutations, PARP inhibitors show promise for breast cancer patients."
It would be interesting to see if PARP inhibitors can benefit those without BRCA mutations, especially since the majority don't have an "obvious" cancer driving mutation.

Fallleaves

Here's a interesting article on the PI3K pathway and cancer metabolism: http://www.sciencedaily.com/releases/2016/01/16012...

Since PI3K inhibitors have a side effect of hyperglycemia, perhaps metformin would be good to combine with it.

Has metformin been tried with PI3K inhibitors?

Also, ran across this study of silymarin (which is I think found in milk thistle) that indicated it could help recover insulin sensitivity and reduce pro-inflammatory cytokines (that drive cancer progression).

http://www.ncbi.nlm.nih.gov/pubmed/24486395

Hopeful82014

Kay, I enjoyed the 'gremlin mutations;' sometimes we need a little unexpected levity - and both terms seem accurate in their own ways.

ChiSandy

I used to be an asssociate in the law offices of Floyd B. Manilow. When we began drafting our own briefs in WordPerfect (rather than having a secretary do it), spell-check kept coming up with “Flood B. Magnolia” instead. (First cousin of “Jubilation T. Cornpone”)?