PSA rising after aberaterone - Advanced Prostate...

Advanced Prostate Cancer

20,782 members25,888 posts

PSA rising after aberaterone

rpol profile image
rpol
23 Replies

I have CRPC heavily metastasized into the bones. I have been on aberaterone for about 9 months. My PSA dropped like a stone from 600 to 22 in Jan, but has climbed slowly now faster to 61 a couple of weeks ago. My question is, can anybody point me to research that may tell me what are the most likely metabolic pathways causing PSA to rise, given that the major PC androgen pathways are blocked by aberaterone? I am on most of the supps recommended in Jane McLelland's book How to Starve Cancer, and started the COC (Care Oncology Clinic) drugs just over a month ago. I am wondering whether I need to hit any pathways harder, or just hope that COC drugs kick in soon.

Written by
rpol profile image
rpol
To view profiles and participate in discussions please or .
Read more about...
23 Replies

I would recommend molecular testing through a company like Foundation One to see if there are genetic mutations driving the resistance such as AR-V7.

NPfisherman profile image
NPfisherman

Since you are on abiraterone and asymptomatic, I would suggest a switch from prednisone to dexamethasone which may buy you time--see below:

ncbi.nlm.nih.gov/pubmed/300...

Also, Indomethacin has been shown to breakdown resistance to abiraterone--see below:

mct.aacrjournals.org/conten...

Try those 2 things and see if it helps--forward the articles to your MO and PCP--one of them should help you out...

Best of luck....

Don Pescado

rpol profile image
rpol in reply to NPfisherman

interesting tho I can only see the abstract of the first article. I know what my onc will say, tho, trials too small. Sigh. May try all the same

NPfisherman profile image
NPfisherman in reply to rpol

Your PCP could help out.... For the first article, try these...

theoncologist.alphamedpress...

ncbi.nlm.nih.gov/pubmed/301...

164 men in this one....

cancernetwork.com/prostate-...

That should be enough to get a trial and see....I would add the indomethacin at the same time and see if I got the drop... Squeeze every minute out of these drugs...

Good luck....

Don Pescado

AlanMeyer profile image
AlanMeyer

I think there are others on this forum who may understand the molecular biology of castration resistance better than I do, but my impression is that the scientists do not yet have a complete understanding of the causes of castration resistance. It's an area of very active and intense research.

One possible cause is that the tumor cells may be manufacturing their own testosterone. Another possibility is that they have become sensitive to even the tiny amount of T which continues to be produced in spite of the abiraterone and other drugs. Still another is that the tumor cells have truly become androgen independent. They divide and multiply even without any T signaling at all.

As I understand it, the fundamental problem is that the tumor cells continue to mutate. When a cell divides all of its DNA must be replicated to occupy each of the two daughter cells. Errors in DNA replication (i.e., "mutations") can occur and, in cancer cells, the error rate can be higher, often much higher, than in normal cells. Tumor cells are, after all, ordinary cells that somehow acquired some serious mutations. So the tumors are "evolving" and just as in other cases of evolution, the cells that out reproduce the rest of the cells eventually come to dominate the tumor cell population.

Here are some ideas that are often proposed to fight castration resistance:

Try enzalutamide (Xtandi), bicalutamide (Casodex), or the new darolutamide that use a different mechanism of hormone therapy. Sometimes these work for a while after abiraterone has failed.

Use drugs that somehow restore hormone sensitivity. Metformin and indomethacin are drugs that are thought to sometimes do this. There may be others.

Use drugs that have nothing to do with hormone sensitivity. Docetaxel and cabazitaxel chemotherapies use a completely different mechanism and can sometimes work. Other non-hormone therapies include radionuclides like Lu-177 and Ac-225 attached to PSMA antibodies can work for men who are "PSMA avid", or immunotherapies like Provenge. It's also possible to try to reverse the evolution of the tumor cells with "bipolar androgen deprivation" (BAT), hitting the tumors with big doses of T in hopes that the cells that have become androgen independent actually can't tolerate T anymore. Still another approach is to try a "PARP inhibitor" that actually increases the rate of mutation in cells. The idea is to hit cells that are already mutating heavily and further increase the rate of mutation in hopes that the tumor cells will mutate to death

I think that most medical oncologists that don't specialize in prostate cancer, and even those who do specialize in it but don't keep up with the latest research, aren't going to be able to advise you on these. You may need to go to one of the research oriented teaching hospitals to pursue these, and maybe enter clinical trials.

The medical research scientists haven't yet solved the problem of castration resistant prostate cancer, but they're trying hard and some of the ideas they have are going to work for at least some patients for at least some time. And there are always the lucky guys for whom one of these tricks works for a long time.

I hope you (and everyone here) manage to get into the lucky guys group.

Best of luck.

Alan

rpol profile image
rpol in reply to AlanMeyer

many thanks for your long list of suggestions. I shall check them all out.

Hirsch profile image
Hirsch in reply to AlanMeyer

Alan...excellent summary of the topic.

Tall_Allen profile image
Tall_Allen

The cancer develops resistance to abiraterone eventually. The AR becomes sensitive to alternative ligands and translocates into the nucleus where it no longer relies on external activation. It also amplifies.

CalBear74 profile image
CalBear74

Dr. Rajesh Agarwal cites the major pathway in a YouTube video involved in Pca. This is in the context of discussing his research on inositol hexaphosphate. He is the most prolific researcher on IP6 and prostate cancer in this country. You can find his publications at pubmed.gov. He is with The university of Colorado school of health sciences Denver.

rpol profile image
rpol in reply to CalBear74

thanks for this lead. Prolific. Not helped by having same name as a Finance Minister somewhere! I have downloaded pubs but have searched in vain for the YouTube video. Can you guide me to it? Sorry to trouble you

CalBear74 profile image
CalBear74 in reply to rpol

I found the video. The pathway blocked by IP6 is P13-AKT. This is a major pathway for prostate cancer. IP6 powder (Enzymatic Therapy) is what I use and purchase from Allstarhealth.com.

youtube.com/watch?v=91f7bur...

These articles will get you started:

Select item 23213071

1.

Inositol hexaphosphate inhibits tumor growth, vascularity, and metabolism in TRAMP mice: a multiparametric magnetic resonance study.

Raina K, Ravichandran K, Rajamanickam S, Huber KM, Serkova NJ, Agarwal R.

Cancer Prev Res (Phila). 2013 Jan;6(1):40-50. doi: 10.1158/1940-6207.CAPR-12-0387. Epub 2012 Dec 4.

PMID: 23213071 Free PMC Article

Similar articles

Select item 19920184

2.

Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target.

Gu M, Roy S, Raina K, Agarwal C, Agarwal R.

Cancer Res. 2009 Dec 15;69(24):9465-72. doi: 10.1158/0008-5472.CAN-09-2805.

PMID: 19920184 Free PMC Article

Similar articles

Select item 19544333

3.

Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells.

Gu M, Raina K, Agarwal C, Agarwal R.

Mol Carcinog. 2010 Jan;49(1):1-12. doi: 10.1002/mc.20560.

PMID: 19544333 Free PMC Article

Similar articles

Select item 19176374

4.

p21/Cip1 and p27/Kip1 Are essential molecular targets of inositol hexaphosphate for its antitumor efficacy against prostate cancer.

Roy S, Gu M, Ramasamy K, Singh RP, Agarwal C, Siriwardana S, Sclafani RA, Agarwal R.

Cancer Res. 2009 Feb 1;69(3):1166-73. doi: 10.1158/0008-5472.CAN-08-3115. Epub 2009 Jan 27.

PMID: 19176374 Free PMC Article

Similar articles

Select item 18483386

5.

Chemopreventive efficacy of inositol hexaphosphate against prostate tumor growth and progression in TRAMP mice.

Raina K, Rajamanickam S, Singh RP, Agarwal R.

Clin Cancer Res. 2008 May 15;14(10):3177-84. doi: 10.1158/1078-0432.CCR-07-5275.

PMID: 18483386 Free PMC Article

Similar articles

Select item 16954429

6.

Mechanisms of action of novel agents for prostate cancer chemoprevention.

Singh RP, Agarwal R.

Endocr Relat Cancer. 2006 Sep;13(3):751-78. Review.

PMID: 16954429

Similar articles

Select item 16080543

7.

Prostate cancer and inositol hexaphosphate: efficacy and mechanisms.

Singh RP, Agarwal R.

Anticancer Res. 2005 Jul-Aug;25(4):2891-903. Review.

PMID: 16080543 Free Article

Similar articles

Select item 15548374

8.

Inositol hexaphosphate inhibits growth and induces G1 arrest and apoptotic death of androgen-dependent human prostate carcinoma LNCaP cells.

Agarwal C, Dhanalakshmi S, Singh RP, Agarwal R.

Neoplasia. 2004 Sep-Oct;6(5):646-59.

PMID: 15548374 Free PMC Article

Similar articles

Select item 14734476

9.

In vivo suppression of hormone-refractory prostate cancer growth by inositol hexaphosphate: induction of insulin-like growth factor binding protein-3 and inhibition of vascular endothelial growth factor.

Singh RP, Sharma G, Mallikarjuna GU, Dhanalakshmi S, Agarwal C, Agarwal R.

Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):244-50.

PMID: 14734476 Free Article

Similar articles

Select item 14666688

10.

Inositol hexaphosphate inhibits constitutive activation of NF- kappa B in androgen-independent human prostate carcinoma DU145 cells.

Agarwal C, Dhanalakshmi S, Singh RP, Agarwal R.

Anticancer Res. 2003 Sep-Oct;23(5A):3855-61.

PMID: 14666688

Similar articles

Select item 14532984

11.

Growth inhibitory and apoptotic effects of inositol hexaphosphate in transgenic adenocarcinoma of mouse prostate (TRAMP-C1) cells.

Sharma G, Singh RP, Agarwal R.

Int J Oncol. 2003 Nov;23(5):1413-8.

PMID: 14532984

Similar articles

Select item 12663518

12.

Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes.

Singh RP, Agarwal C, Agarwal R.

Carcinogenesis. 2003 Mar;24(3):555-63.

PMID: 12663518

Similar articles

rpol profile image
rpol in reply to CalBear74

many thanks. Just to clarify, can you confirm that P13-AKT pathway is NOT closed down by androgen deprivation (i.e. abiraterone)?

CalBear74 profile image
CalBear74

ADT is a category of treatment not a specific drug, therefore it would be unlikely that any researcher would state with certainty that ALL drugs impact that pathway or fail to. As for abiraterone, check the Published research.

Alas everything we do slows down or stops working after a while. Those clever little bastards have a Plan B, C, D, E ....Z - so we have to change our plans too and keep ahead if we can. Remember it is you immune systems (try a raw food diet to make them stronger) that have to kill the cancer - the medications only slow it down. But something does not seem to "add up" in your meds.

It is my understanding that Abiraterone does not block testosterone (T) uptake - it inhibits the production of T. I see 3 parts to this problem - stop production of the T in the testes using Lupron (or similar ADT); if that does not drop the level enough then Abiraterone (Zytiga) is often added as that also inhibits testosterone production in the adrenal gland (it also affects other production, so you have to replace the missing hormones with prednisone etc.). With both these processes in action, the T will be very low. The third thing to do is to block the T receptors on the cancer cells - Bicalutamide works for some, but tends to have a limited effective life span and can have nasty side effects after a while. Xtandi (enzalutamide) is a more powerful blocker.

I am puzzled that you are not on Lupron as the "front line" treatment, as that is what just about all of us are on (or were on at some time).

Clearly the effective life span of the abiraterone treatment has come to an end. I would suggest trying Xtandi as your next weapon of choice (and/or Lupron???). I don't think you need to look for exotic mutations and "resistance" at this time - your numbers can be explained with the normal varieties. Good luck!

rpol profile image
rpol in reply to

I have been on Lupron 3 monthly jab since diagnosed in late 2017, and was told to continue this for life

in reply to rpol

Ah! I like it when 1+1=2. That leaves Xtandi to try.

rpol profile image
rpol in reply to

I am sure I have read somewhere that once you have had abiraterone then you cannot have enzalutamide and v v. So Xtandi is not an option.

in reply to rpol

If that is the case where you live, get on an airplane and go where the price is cheaper (change pays for the flights and beach hotel), and add some Vit C via IV while you are there. There is also a stupid rule in some countries that you have to have had chemo before Xtandi (but the rule is being ignored). I don't know how they find these idiots! This "Industry" is plagued by archaic thinking and rules to avoid malpractice suits - and it is killing people by creating malpractice. But that's OK if "by the book".

I have been using low dose Xtandi for 21 months now, and can assure you it is quite tame in its side effects, and works fine with Lupron. There are lots of men in this forum doing that combo in preference to the Lupron/Zytiga combo.

Or, try shouting and keep it up until the problem goes away. The more people that can hear you, the quicker the surrender to make a plan.

Shanti1 profile image
Shanti1

You may find this paper informative, it discusses the ways prostate cancer metabolism deviates from normal cell metabolism: ncbi.nlm.nih.gov/pmc/articl....

If you are trying to use a metabolic approach to cancer, this paper provides targets specific to prostate cancer. For example, using a zinc ionophor can help to restore intracelular zinc which inhibits the aconitase enzyme and therefore the Kreb cycle. Prostate cancer favors krebs cycle/oxidative phosphorylation over fermentive glycolysis, at least initially. This approach is discussed here and is also a part of the following case study:

ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/pmc/articl...

Hydroxycitrate may also be very relevant, it inhibits ATP citrate Lyase, which is needed for intracellular fatty acid synthesis, which prostate cancer uses for fuel and new cell construction. More info here: cancertreatmentsresearch.co.... There are other things to target as well. Anyhow, I don't think these are cures, but may slow the beast down. My feeling is, it is worth trying. Best to you.

rpol profile image
rpol in reply to Shanti1

thanks Shanti1. I have read and reread the metabolic phenotype paper, a month ago, but I am clearly late stage PCa, not initial. I have lupron jabs regularly, had 6 cycles of chemo, now months of abiraterone, each of which initially knocked down my PSA from something huge (960 before chemo, 600 before abi) to something reasonable. But now it is taking off again. I am indeed wondering what I can do beyond COC drugs + many supps to slow the beast down. I would love to think COC can stop PSA rising, but suspect I need to add in other stuff. IV vitC is certainly one route that keeps cropping up. Still doing my homework, but thanks for your suggestions.

Philly13 profile image
Philly13

What about other test results from comprehensive metabolic blood work? Are there any other signs of cancerous growth?

Philly13 profile image
Philly13 in reply to Philly13

I am not implying that your PSA indicates cancerous growth. Many on this site watch more than one marker.

rpol profile image
rpol in reply to Philly13

extensive bone mets but not clear whether they are getting worse over 2 years. No obvious progression on CT scans

You may also like...

Rise in PSA after Radiation

antioxidants. during Radiation treatment. A month ago my PSA was 21 and now it’s at 37. I am...

PSA Rising After Chemo

latest PSA test and it was not good news. I finished my last chemo treatment in May and my PSA has...

Rising PSA After Treatment

August 2017 - psa 2.20 22 Sept 2017 - psa 2.35 16 Jan 2018 - psa 4.94 Does anyone have experience...

Docetaxel after rising PSA

a docetaxel cure (6 x 3 weeks) in a few months (PSA is rising a lot after 4 years of Zytiga). Do...

Rising PSA after Prostatectomy

2018 at the age of 55 with a gleason score 7. My PSA test 0.02 8/10/18, 0.03 3/1/19, 0.04 5/3/19....