Study finds breast cancer's response to tumor stiffness may predict bone metastasis

Tumor stiffening, which develops as diseased breast tissue becomes fibrotic, plays a major role in how breast cancer cells spread throughout the body. The paper, "Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning," published today in the journal Cell Reports, found that the stiffness of the breast tumor microenvironment can cause changes to cancer cells that make them more aggressively spread to the bone. The resulting changes are maintained as "mechanical memory," which instructs the cancer cells to send signals that lead to the breakdown of bone. Once this happens, patients often suffer debilitating complications like spontaneous fractures...

The study, which is the first to demonstrate the concept of mechanical memory during cancer metastasis, developed a novel mechanical conditioning, or "MeCo," score, to quantify the cellular changes. Eventually, researchers hope the MeCo score can be used to help identify breast cancer patients who might benefit from repurposed antifibrotic treatments to prevent bone metastasis.

https://www.eurekalert.org/pub_releases/2021-06/uo...

[Early research] RNA-binding proteins represent a new class of drug targets for triple-negative breast cancer

The researchers systematically silenced RNA-binding proteins in these cancer cells one-by-one using the CRISPR gene editing technique. They found 57 RNA-binding proteins that, when inhibited, kill cancer cells with the known hyperactive cancer-driver. The advantage of the synthetic lethal approach is that normal cells, which don't produce that cancer-driving molecule, should be left untouched by the treatment. Of these 57 RNA-binding proteins, YTHDF2 appeared most promising...

The researchers [got a] detailed look at how the various cells that make up a breast tumor behave without YTHDF2. The approach revealed that YTHDF2-deficient cancer cells die by stress-induced apoptosis, a carefully controlled mechanism cells use to destroy themselves. Apoptosis is supposed to shut down malfunctioning cells so tumors don't arise, but it doesn't always work. By removing YTHDF2, they managed to re-activate this cell death signal.

To test how safe it might be to treat cancer by inhibiting YTHDF2, the researchers engineered mice that lack YTHDF2 in every cell of the adult body, not just transplanted breast cancer cells. The mice appeared completely normal -- not only did they not have tumors, there were no changes in body weight or behavior.

https://www.news-medical.net/news/20210702/RNA-binding-proteins-represent-a-new-class-of-drug-targets-for-triple-negative-breast-cancer.aspx

HomeMom,

I had the wrong link for the last article I posted. I've fixed it now. The testing was done on TN BC using human cells and mouse models. The study identified an RNA-binding protein which was needed for the cancer cells to survive but not needed by normal cells. The next step would be to target this protein with a drug.

ETA: Here's a more detailed article that came out today: https://www.genengnews.com/news/rna-binding-protei...

Oral paclitaxel may still be a future option despite being denied FDA approval a few months ago. "The FDA was supportive and encouraged the Company to continue development of oral paclitaxel and encequidar for the treatment of metastatic breast cancer. The FDA also agreed that a well-designed and well-conducted trial may adequately address the deficiencies raised in the CRL." https://www.obroncology.com/news/athenex-provides-update-from-fda-type-a-meeting-regarding-oral-paclitaxel?ap=334&vhid=

Interesting article LIllyishere

great article about oligometastes and local treatment

https://ascopubs.org/doi/full/10.1200/JCO.21.00445

Oligometastases (<=5 lesions in one location) is getting more attention and guidelines.

The treatment of patients with oligometastatic disease is and must remain individualized and based on multidisciplinary decisions.

size could become part of the definition: metastatic lesions should be considered oligometastatic (ie, potentially eligible for local treatment) only when the size of the smallest lesion has reached a certain threshold, which could be proposed around 8-10 mm in diameter

Dee

Guys, from what I read and see around, de novo multiple involvement/progression in one organ might also be seen as oligo-disease, as usually these tumors, although abundant, are of a very uniform genomic setting and systemic treatments, if they work, they work for all tumors. So, this has nothing to do with local treatments, but with definitions of what oligo might be in the future. Maybe they will come up with another term too. Saulius

cowgal- If I understand the article, they are looking at the age of the tumors as represented by the tumor growth/size. The thought is if the smallest tumor is less than 8mm diameter it is not mature and there could be others lurking close by. If the smallest tumor is greater than 8mm then there is more confidence of oligometastes due to the tumor cell doubling time. Which would potentially qualify you for the local treatments. It's a bit confusing but still progress in some ways.

Olma was not in that parameter but responded. I was in that category but was refused surgery at MDACC -they insisted on a systemic working first. Can’t look back though

BSandra-good point.

Dee

Moth, Dee, these articles never really explain how they define that something is oligo. What they want to say probably is that oligo-lesion is sort of in-situ metastatic tumor. But if it is not in-situ, then it is invasive, and even several mm can contribute to further spread (as also noted in the article), so I do not get the idea of "waiting". You notice a lesion that is 2 mm, and then wait until it is 8 mm, and then suddenly other 2 mm satellite lesions occur nearby because of that 8 mm lesion, and then you are like "you were curable 2 months ago but now, ups, you are incurable, sorry". Would it not be smarter to start asap with treatment of 2 mm lesion and then see if others pop-up? This way most more patients would be cured: those who are "oligo", and those who aren't "oligo" but whose tumor did not spread into surrounding environment. I never liked the "oligo" hypothesis. Too many flaws and no real criterion to define it. One of the flaws again is the denial of "oligo-progression". What if someone has achieved pCR in distant organs, and not in initial tumor (a few undetected cells left), and then initial tumor once again metastasizes with only few lesions in the beginning and they are detected? Saulius

You see, Dee, you are a real example. Now take the scenario if your lung nodule would have not been treated (I am pretty sure your lungs would have progressed more as that lesion came up being under treatment)... but it was treated and today we see that decision was absolutely correct, although according to oligo-hypothesis you did not fall into "oligo" a category and would have not qualified for local treatments. From what I read, whether lesions are 5, or 25, if the drug/local treatment works, they can be obliterated, so "oligo" (meaning "few") does not make sense, as well as waiting - not only primary tumor causes metastases but also metastatic tumors spread further, so why wait? Stage 3C (let's say it is some stage 3.5:) is curable in practice with multiple lymph node metastases and has survival rate of ~40% at 15 years, so maybe some stage 4 are also more like 3.8, and also are curable, therefore you cannot give up on any patient and curative strategies have to be in mind as much as possible. There might be a huge difference between, let's say, these two cases: case 1 - T4N3M1 with 3 genetically nonuniform metastatic lesions >1 cm in the liver, and case2 - T4N3M1 with 20 genetically uniform (for example, de novo) metastatic lesions <1 cm in the liver. Oligo theory says that case1 has more chances for a cure than case2, but actually there's no real evidence for that, as we do not know genomic arrangement of every lesion or micromet. Just remember - we usually biopsy 1 or 2, and then give treatments, and they don't work. Why? Most probably because disease is nonuniform, and remaining 3 mets have different genomic arrangement. Local treatments "do not care" of non-uniformity, and that is why they are amazing. Our immunologist said surgery lives its golden age - he said, if I recall correctly, Norwegians cyberknifed 120 metastases in one person's lung, and the person is alive and doing ok, so actually local treatment possibilities have a big future and some 20 lesions with image recognition and AI a few years ahead might be an "easy" surgery.

I also love these discussions but I think professionals would be reluctant to discuss such things - they are too afraid to be viewed as unprofessional!:) Saulius

Great analysis, guys! Interesting discussion

Dear Dee, wow, I cannot believe MDACC said no to surgery. Potential micromets, I understand, but still... crazy... Saulius

CP418 - Wow, great article! I would love to sign up for a clinical trial.

Sounds very interesting but the BBC article I saw on it said that if it all goes well, it should be available in a DECADE!!! Seriously?! Why should it have to take that long when they got a vaccine for a novel coronavirus out in under a year. Why cant they move it along faster and let those with no other options to take a chance on it? the covid vaccine got an emergency approval. Couldnt they do that with a cancer treatment like this?