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-   -   Tivatinib (ARQ-197) (https://her2support.org/vbulletin/showthread.php?t=59920)

donocco 01-02-2014 11:46 PM

Tivatinib (ARQ-197)
I dont know if this investigational drug has been mentioned before. It is an inhibitor of C-MET which is the Hepatocyte Growth Factor Tyrosine Kinase. Apparently C-Met is overactive in various cancers. Tivatinib has been tried in Non Small Cell Cancer of the lung and Hepatocellular Carcinoma with some positive results.

The usual dosage seems to be 360mg twice daily and the side effects are anemia, Neutropenia, Fatigue and appetite loss.


donocco 01-03-2014 12:23 AM

Re: Tivatinib (ARQ-197)
I found another article I xeroxed from the Pharmacy I last worked at about ARQ-197 (Tivatinib).

For one thing there were some prolonged stablization of disease when ARQ-197 was given in Pancreatic cancer which often has a quick clinical course. Ill have to search the for specific articles.

As far as breast cancer goes in pts treated with Herceptin and given ARQ-197 experimentally, the incidince of brain mets in one study was more than halved. It seems ARQ-197 has antimetastatic activity.

The list of side effects was more extensive.

Fatigue was most common (about 21%), Nausea (10%)
Diarrhea (6.4%), chills (4.3%), night sweats (4.3%)
Taste disturbances (4.3%), Decreased appetite (4.3%)
Neutopenia (2.1%), Anemia (2.1%) and increased liver enzymes (2.1%)


'lizbeth 01-03-2014 09:48 AM

Re: Tivatinib (ARQ-197)
This one is new to me, but I am thrilled to hear of any treatment that blocks mets, especially to the brain.

dita 01-03-2014 07:57 PM

Re: Tivatinib (ARQ-197)
Thanks for posting Paul. Can you tell me a little more about it- is it a targeted therapy and does it work in combination with herceptin? Is the idea that it works on all types of bc or only her2?

donocco 01-03-2014 10:59 PM

Re: Tivatinib (ARQ-197)
Ill do some research on it. What i put down was very preliminary. I sent an article on the Hepatocyte Growth factor to my wife's computer at work and Ill read it tonight. Tivatinib or ARK-197 inhibits the Kinase enzyme in the receptor that the Hepatocyte Growth Factor attaches to. When I get a better understanding of the action of the Hepatocyte Growth Factor, Ill have a better understanding about Tivatinib. It seems the more you learn about something the more questions come up.

One of the names for the Hepatocyte Growth Factor is C-Met and Met stands for mesenchymal-to epidemal transformation. Cancer cells have to change shape before they start spreading. Once they change shape they become more motile and can spread. This is a guess about C-Met but I may be on track. If Im wrong Ill correct this.

To answer your question Diva its not just breast cancer or primarily breast cancer. In order for Tivatinib to be effective there apparently has to be an overactivity of the C-MET Tyrosine Kinase. This occurs in about 80% of Pancreatic cancers, I don't know what percentage of breast cancers, or if C-met is more active in, say, triple negative breast cancer, or Her2Neu positive breast cancer. Ill see what I can find.

Tivatinib seems to be an interesting drug. It must cross the blood brain barrier to be a preventitive against HER2positive brain mets. Ill post the information I can find. It seems to be worth spending some time with this drug.


donocco 01-05-2014 04:11 PM

Re: Tivatinib (ARQ-197)
I read the article on C-MET and learned a lot. I dont know if it would make sense putting it on the board. Its sort of an A-B-C-D-E-F thing, A being C-met which is connected to another protein (B) which is connected to another protein (D) which is conncected to all the other proteins and after F you get a reaction, be it increased cancer cell growth or increased cancer cell motility. To make it more complicated, protein B might stimulate Protein C1 and you have a different cascade that branches out. There are so many connections and interconnections and branches and subbranches, it can make your head spin. This is called signal transduction and is one of the reasons finding effective treatments for cancer is so complicated. If you block one pathway, a different one can take its place. Im still researching Tivatinib. The C-met (hepatocyte growth factor receptor is located in the cell membrane (like the Her-2 receptor) and the B,C,D,E F protein connections go deeper into the cell and eventually effect the cell nucleus.


'lizbeth 01-05-2014 05:01 PM

Re: Tivatinib (ARQ-197)
You could post it under articles of interest.

It shows how looking for one magic drug to cure cancer is unrealistic, a combination or a strategic order of treatments is the key - including boosters.

We are lucky current science is moving beyond trials of chemo, more chemo, which chemo to targeted therapy, more targeted therapies & which targeted therapies.

It does sound very complex. Thanks for decoding the information.

donocco 01-05-2014 07:01 PM

Re: Tivatinib (ARQ-197)

Since you are interested in this Ill show you how complicated it gets. Affinitor is an anticancer drug that inhibits M-Tor. There are two froms of M-Tor and Affinitor mostly inhibits M-Tor1. When you inhibit Mtor1 you inhibit what are called S6 Kinases. This is good in treating cancer because, in simple language, S6 Kinases stimulate cancer cell growth.

But inhibiting S6 kinases by inhibiting M-Tor also causes a problem. When S6 Kinase is inhibited, a protein called AKT becomes more active and AKT activates M-Tor. So by inhibiting S6 Kinases by inhibiting M-Tor you eventually re-stimulate M-Tor all over again by activating AKT. You can see why this material makes your head spin.

I started talking about C-Met or Hepatocyte Growth Factor Receptor. Activating C-Met activates a protein called GAB1 and GAB1 activates a protein called P13K and P13K activates AKT and AKT activates M-tor1 and M-Tor1 activates S6 Kinase and S6 Kinase stimulates cancer growth. By blocking Mtor1 you block S6 Kinase and as far as cancer treatment goes, that is a good thing. But blocking S6 Kinase overactivates AKT and you end up with more than normal M-Tor1 action. Its like a loop that goes round and round.

Since P13K stimulates AKT, maybe by combining an M-Tor inhibitor like Affinitor with a P13K inhibitor like BMK-120 (known as Buparlisib, an investigational drug), you can get the positive anticancer activity of an M-Tor inhibitor without restimulating more M-Tor activity in the cell. You can see how complicated this is.


PS P13K acivity is important in insulin action in normal cells. This must be why the P13K inhibitors like BMK-120
have high blood sugar (hyperglycemia) as a common side effect.

'lizbeth 01-06-2014 09:52 AM

Re: Tivatinib (ARQ-197)
Wow, that is a great explanation. To be honest, the identifiers for all the pathways were starting to look more like alphabet soup.

So, everything in moderation - including treatments, or the solution becomes the problem.

I see about using a P13K inhibitor with an M-Tor inhibitor.

Alaska Angel mentioned metformin, how would that effect some of these processes?

donocco 01-06-2014 05:27 PM

Re: Tivatinib (ARQ-197)

If you think of it like the alphabet it becomes less formidble. To say P13K to AKT to MTor is just like saying A B C.

Your idea of a P13K inhibitor makes a lot of sense. There is one in the pipeline called Buparlisib or BMK-120.
There is another problem though. The signal transduction (P13K to AKT etc doesnt just go downstream. It also goes upstream.

Usually AKT activates Mtor, but MTor has 2 forms 1 and 2. Drugs like affinitor inhibit form 1 and dont have that strong an effect on MTOR-C2 or form 2. MTor-C2 can act upstream and activate AKT. So even blocking P13K isnt the whole answer. We need Mtor inhibitors that are effective against both forms of M-Tor.


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