cancer drug inhibits DNA repair in cancer cells

[George71]

"But the combination of cediranib and olaparib was effective in ovarian cancer that did not have BRCA1/BRCA2 mutations—leading to the launch of several clinical trials testing the drug duo in different types of cancers, including prostate and lung cancer.

Glazer and his team wanted to understand how cediranib exerted such a powerful effect.

Researchers thought cediranib worked in that clinical trial by shutting down angiogenesis, the stimulation of blood vessel growth. Blocking angiogenesis leads to low-oxygen conditions inside tumors, sometimes called hypoxia. Two decades ago, Glazer demonstrated that, among other things, low oxygen seemed to negatively affect DNA repair. In short, the researchers believed hypoxia caused by cediranib led to weak DNA repair.

But what the new study found is that while cediranib does help stop growth of new blood vessels in tumors, it has a second—and potentially more powerful—function. It switches off DNA repair at an early stage in the DNA repair pathway. "Unlike olaparib, it doesn't directly block a DNA repair molecule, stopping DNA from stitching itself back together. It affects the regulation by which DNA repair genes are expressed," said Glazer.

Cediranib makes tumors more sensitive to the effects of olaparib because it stops cancer cells from repairing their DNA by a mechanism called homology-directed repair (HDR). This occurs when a healthy strand of DNA is used as a template to repair the identical, but damaged, DNA strand, he added.

Cediranib's direct effect comes from inhibiting the platelet-derived growth factor receptor (PDGFR), which is involved in cell growth. The drug, therefore, works to inhibit both angiogenesis and the ability of tumors to grow by repairing mishaps in their DNA. "The capacity of the drug to harm blood vessel formation was not a surprise. But its direct effect on DNA repair through the PDGF receptor was completely unexpected," Glazer said."

medicalxpress.com/news/2019...

[tennis4life]

"leading to the launch of several clinical trials testing the drug duo in different types of cancers, including prostate and lung cancer."

Hmmmmmm, I wonder what trials are taking place for this combo. Too tired tonite to look it up. But sounds fascinating.

[NPfisherman]

Nice find, George71...as previously discussed, combination of drugs looks to be the wave of the future in blocking tumorigenesis, killing PCa cells, and obtaining much longer remissions--PFS, OS, etc...look for them to mix SBRT into this...I am a walking experiment myself--Z/P + Lupron and SBRT early...hoping it will leave my PSA "undetectable" for a while... will be adding Dukoral vaccine to the mix in June... we are all walking PCa experiments... LOL....

Fish

[Schwah in reply to NPfisherman]

I’m on everything you are (including the SBRT) plus did four rounds of chemo and zometa with Celebrex. Down to .01 and just started a “vacation”. But I’ve not heard of Dukoral vaccine. What’s that ?

Schwah

[NPfisherman in reply to Schwah]

Brother, you have heard of it,,,, you posted on this 4 months ago....it is the Cholera vaccine--2 oral doses several weeks apart...it was a Swedish epidemiological study, where individuals given the vaccine post PCa diagnosis had longer OS--it is being looked into for Colorectal cancer currently....can get it in Canada for like $110....

The Lupron makes me forget stuff..... maybe you too... no worries... you can google Dukoral and prostate cancer... No Phase 3 studies....Nalakrats says it interferes with mRNA of PCa...

All the best,

Fish

[Schwah in reply to NPfisherman]

Yes I did. Lupron brain. Thank you. How did you get the vaccine ? Any side affects or risks associated that you can find? My MO (dr Scholz) who is willing to push the envelope (taxotere and Zytega and SBRT) doesn’t like the structure of the study. He thinks wealthier , healthier people travel and get the vaccine. The study claims to adjust for that, so if there’s no real downside I think I may add it to the regimen. Did you have any hesitation about using it?

Schwah

[NPfisherman in reply to Schwah]

Haven't used it yet...got a fishing trip planned near the Canadian border and will grab it then...No Rx needed...You can google locations near you in Canada for Dukoral vaccine.... George71 has had the vaccine and you can message him about his experience...I am not worried about the SE though--from the Mayo:

mayoclinic.org/drugs-supple...

Take care, brother...

Fish

[George71 in reply to NPfisherman]

over the counter med .. very safe -- I had zero side effects -- raspberry powder -- mix with 6 oz water and drink wait a week and do another pack -- good for 18 months to 2 years -- children 2 years old can take it -- they take 3 packs.

If I recall correctly -- the inner pamphlet said it could be stored un-refrigerated for 2 weeks one time - then keep refrigerated. I brought it back in carry on bag with ziplock bag of ice from airport concession station.

[j-o-h-n in reply to George71]

Sounds like jello powder... Does it slosh around when you drink it?

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 05/31/2019 7:18 PM DST

[Schwah in reply to NPfisherman]

Thank you my friehd for your quick response. By the way was my original post what prompted you to consider the vaccine or had you heard of it elsewhere ? What did your MO say are are you not bothering to even ask ? I’m a gambler anyway by nature and this Seems like a good risk reward scenario.

Schwah

[NPfisherman in reply to Schwah]

I am not asking...when I take supplements daily, I talk with the PharmD , but on a one time dose of something then no....I had read another post....did the research and felt it to be a safe gamble ....especially, since I travel abroad sometimes.... went to Dominican Republic once and wish I took it then...in the bathroom for days.... never go back there...

Everyone chooses to gamble here and we are betting our lives....I think you have a strong regimen with Xometa and Celebrex plus you were on all the stuff I am on...Enjoy the ADT vacation...Hoping for a long remission for you/ cure......Good luck...it lifts the spirits to think of brothers escaping this hell ship--the SS APC... I have 4 brothers I am praying for and put a prayer into the Wailing Wall in Israel for recently that also have a chance to escape... May God grant you all mercy and a cure...

Fish

[Schwah in reply to NPfisherman]

Thank you Fish. I hope to someday also travel to Israel and the home of my ancestors and pray at the wailing wall. Shalom. Seems like a lot of Jews here. Wonder if our genes make us more prone to PC ?

Schwah.

[NPfisherman in reply to Schwah]

I do not have the honor of being Jewish....LOL... the wife however is a different story...it is a fabulous country with so much history...1st the Canaanites, Philistines, etc...then the Exodus with the children of Israel coming to the Promised Land....then the Babylonians, the Persians, the Romans, the Byzantine period, the Moors, the Crusaders, The Moors again, later---the British and at last.... Israel...

Tel Aviv, Haifa, Jerusalem--the new and old, Dead Sea, Jordan River, Sea of Galilee...Masada....so many things to see and experience...All the best, my man...

Shalom...

Fish

[snoraste in reply to NPfisherman]

I was checking to see if the vaccine is any clinical trials, but could not find. If the HRs are near what the population study suggests, the Onc community should be all over it. The vaccine seems to be fairly safe on its own. My only concern would be if using this vaccine, also "vaccinates" the cancer cells, leading to new form of mutation that is resistant to a more potent immunotherapy down the road. But you never know. There's been a case of complete remission via Measles virus.

[NPfisherman in reply to snoraste]

We're all gamblers--it is getting more interest in colorectal cancer for now...like everything else, give it time...

Fish

[NPfisherman in reply to snoraste]

Nalakrats said (and he may have read a paper) that the vaccine messes up mRNA of the tumor cells and affects tumorigenesis.... I can't wait for a clinical trial to happen...that could take 10 years or more....rollin' the dice...

Fish

[monte1111 in reply to Schwah]

Just took a Prostate Cancer survey (for Erleada). One of the questions was are you Jewish. I am not. Didn't even think about it till your comment.

[j-o-h-n in reply to NPfisherman]

I can tell you forgot to include my prayer note about restoring my sex life....Still with Dolly...

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 05/31/2019 7:23 PM DST

[NPfisherman in reply to j-o-h-n]

I am the Lupron Don....mess with me and desire goes out the back window....you and that wack, Dolly are off the hook, bro... Remember, God answers prayers as per his will, not ours...

Don Pescado

[j-o-h-n in reply to NPfisherman]

to: Don Luprono Pescado

Desire??? What the hell is that? Sounds like some kind of a streetcar to me....

His will....??? I think you meant Her will... It's the time of the ♀️

Dolly sends her regards...

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 05/31/2019 8:08 PM DST

[monte1111 in reply to NPfisherman]

Thank you sir. Made my day. Why do we even bother with chemo and all of these drugs, when we can go to the Dominican Republic and get the same effects. I do so hope the bathroom had one of those little fans.

[NPfisherman in reply to monte1111]

Thankfully....it did....the wife was sick too....Guess they knew in advance to put those fans in for the gringos getting traveler's diarrhea...lucky me... <grin>

Don Pescado aka Fish

[Litlerny]

Good info, George. Thanks for the post. Apparently, neither Olaparib or Rucaparib have any efficacy for patients with an ATM gene mutation. I’m wondering if Cedaranib does.