Thursday, May 12, 2016

New Target for TNBC Found, Say UC Berkeley Researchers

University of California, Berkeley researchers have found a long-elusive Achilles’ heel within “triple-negative” breast tumors, a common type of breast cancer that is difficult to treat. The scientists then used a drug-like molecule to successfully target this vulnerability, killing cancer cells in the lab and shrinking tumors in mice.

“We were looking for targets that drive cancer metabolism in triple-negative breast cancer, and we found one that was very specific to this type of cancer,” said Daniel K. Nomura, an associate professor of chemistry and of nutritional sciences and toxicology at UC Berkeley and senior author for the study, which is published online ahead of print on May 12 in Cell Chemical Biology.

Triple-negative breast cancers account for about one in five breast cancers, and they are [Pat's edit: "they may be"] deadlier than other forms of breast cancer, in part because no drugs have been developed to specifically target these tumors
Triple-negative breast cancers do not rely on the hormones estrogen and progesterone for growth, nor on human epidermal growth factor receptor 2 (HER2). Because they do not depend on these three targets, they are not vulnerable to modern hormonal therapies or to the HER2-targeted drug Herceptin (trastuzumab). 

Instead, oncologists treat triple-negative breast cancer with older chemotherapies that target all dividing cells. If triple-negative breast cancer spreads beyond the breast to distant sites within the body, an event called metastasis, there are few treatment options.

Tumor cells develop abnormal metabolism, which they rely on to get the energy boost they need to fuel their rapid growth. In their new study, the research team used an innovative approach to search for active enzymes that triple-negative breast cancers use differently for metabolism in comparison to other cells and even other tumors. 

Inhibiting cancer metabolism
They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

Co-author Eranthie Weerapana, an associate professor of chemistry at Boston College, developed a molecule named LAS17 that tightly and irreversibly attaches to the target site on the GSTP1 molecule. By binding tightly to GSTP1, LAS17 inhibits activity of the enzyme. The researchers found that LAS17 was highly specific for GSTP1, and did not attach to other proteins in cells.

According to Nomura, LAS17 did not appear to have toxic side effects in mice, where it shrank tumors grown to an invasive stage from surgically transplanted, human, triple-negative breast cancer cells that had long been maintained in lab cultures.

The research team intends to continue studying LAS17, Nomura said, with the next step being to study tumor tissue resected from human triple-negative breast cancers and transplanted directly into mice. 

“Inhibiting GSTP1 impairs glycolytic metabolism,” Nomura said. “More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells.”

Beyond the metabolic role they first sought to track down, GSTP1 also appears to aid signaling within triple-negative breast cancer cells, helping to spur tumor growth, the researchers found.

Technique identifies Achilles' heels
Nomura said it was surprising that a single, unique target emerged from the research team’s search. 
The method used by the researchers, called “reactivity-based chemoproteomics,” can quickly lead to specific targetable sites — the Achilles’ heels — on proteins of interest, and eventually to drug development strategies, Nomura said.

The approach is to search for protein targets that are actively functioning within cells, instead of first using the well-trod path of surveying all genes to identify the specific genes that have taken the first step toward protein production. With that more conventional strategy, the switching on, or “expression,” of genes is evidenced by the easily quantified molecule called messenger RNA, made by the cell from a gene’s DNA template.
Nomura’s team instead first used chemical probes that can react with certain configurations of two of the amino acid building blocks of protein — cysteine and lysine — known to be involved in several kinds of important structural and functional transitions that active proteins can undergo.

 “A lot can happen after the first step in protein production, and we believe our method for identifying fully formed, active proteins is more useful for tracking down relevant differences in cellular physiology,” Nomura said.
The researchers analyzed and compared cells from five distinct triple-negative breast cancers that had been grown in cell cultures for generations, along with cells from four distinct breast cancers that were not triple negative. 

The scientists used a chemical identification technique known as mass spectrometry to narrow down the set of proteins that had active lysines and cysteines to just those that were metabolic enzymes. Only then did they use the more conventional approach of measuring gene expression in the different cancer cell types.

GSTP1 was the only metabolically active enzyme that was specifically expressed only in triple-negative breast cancer cells compared to other breast cancer cell types, the researchers found. Separate analysis of databases of human breast cancer by UC San Francisco co-authors confirmed that GSTP1 is overexpressed in patients with triple-negative breast cancers in comparison to patients with other breast cancers.


Joy Svenson said...

This is huge, why isnt it on the news... this is great!

Patricia Prijatel said...

I just got the release, so maybe it will make it. Still, TNBC is not exactly a media darling. Also, the research is in mice, which means it will take a few more steps before we know if it will work in humans.

Joy Svenson said...

I am so happy, a target...I posted it on my site for my girls. I also posted it on a couple more but they are just asking when are trials, I know for some they fear it wont be in time for them. Just breaks my heart....but it seems so promising!

Patricia Prijatel said...

I've thought for some time that we are on the cusp of a new treatment. So something might happen soon with other research. Lots is going on, finally, with TNBC research.

Unknown said...

I was going to buy the vitamin Glutathione, does this mean I shouldn't take it????

Anonymous said...

I lost my beautiful Shani in January to this dreaded cancer. I am so hopeful for a targeted treatment. I only wish something would have came along several years ago. But anything that could help anyone else not suffer would be great. The immuno therapy drugs look promising as well. We will keep praying for something good to happen.

Patricia Prijatel said...
This comment has been removed by the author.
Joy Svenson said...

Patricia how glutathione good after this report ? Thanks I have some woman worried!

Patricia Prijatel said...
This comment has been removed by the author.
Patricia Prijatel said...

I am not a fan of taking vitamins in general, but advocate natural sources for healthy nutrients when it is possible. Lots of research has shown that eating fruits and vegetables is especially important in combatting TNBC and that cruciferous vegetables can reduce the risk of TNBC. But glutathione is in cruciferous vegetables. So, does this research counters those previous studies? We don't know yet, but I suspect not. I suspect the truth will end up being far more complicated and will come down, once again, to individual reactions, to our cancers being as unique as our DNAs. So my advice is to eat your fruits and vegetables, including the cruciferous, which includes broccoli and cabbage and kale, but not take vitamin supplements because the latter are too concentrated and might not offer a natural balance. If you are worried, then cut down on the amount of cruciferous veggies, but still eat lots of other fruits and veggies. Still, you might contact the researchers and get their take. At this point, I think the takeaway is: Yay! We might be finally close to that target, the drug for TNBC that does what Herceptin does for Her2-positive. Let's wait until the actual mechanics are clearer.

Joy Svenson said...

Her is the response I recieved.Its a generic letter sent to anyone who inquires.
Dear Joy,

Thanks for your interest in our study. We discovered a new TNBC drug target called GSTP1 that regulates glucose metabolism in TNBC cells. We've been able to show that we can regress TNBC tumor growth in mice with GSTP1 inhibitors through impairing glucose metabolism in TNBC cells that feeds into lipid and nucleotide metabolism that the cell needs to make cell membranes and DNA necessary for cells to proliferate. We hope eventually to translate GSTP1 inhibitors into the clinic but this will take many more years.

It is for people like you that our lab works hard to try to develop new treatments and hopefully cures for TNBCs.

You can read more about our study on our lab website:

Patricia Prijatel said...

Generic indeed. Ugh.