chemo 'feeds' bone met tumors?!!: "Chemotherapy induces JAG1 expression in osteoblasts, promoting chemoresistance in bone metastases"

[JLS1]

Does anyone have access to this article?

It sounds like the chemo, Docetaxel, which my husband finished last July, may not have helped the tumors in his spine and instead were 'feeding' them?!!!

cancerdiscovery.aacrjournal...

Targeting JAG1 Sensitizes Bone Metastases to Chemotherapy

I suspect this may be why my husband is suddenly having serious pain in his lower spine causing him to be incapacitated. He's scheduled for radiation treatments beginning next week to help shrink the tumor growing in his spine, which is pressing on his sciatic and femoral nerves.

Background:

Last Feb, 2017, my husband (age 60), was diagnosed with metastatic prostate cancer with many mets to his bones (spine, skull, ribs, femur). This was a shock as he had no unusual symptoms until a lesion in his skull effected his tongue (beginning Jan 13, 2017) Prior to that, his only other symptoms were bone pain that didn't seem unusual for someone his age who spends hours sitting, working on the computer). A wonderful neurologist had him immediately admitted to the hospital and given a complete work up with MRIs, CT scans, blood tests, etc and except for all the bone mets and slightly elevated alk phosphate levels, Dr's said he appeared to be a very healthy man. His PSA was elevated, but not alarming - 5.8. (it rose to 18.76 on March 7th, before starting chemo) They were stumped and unable to diagnose until a couple weeks later when the bone biopsy revealed the shocking St4 prostate cancer. By mid Feb.,, right before we went to a new oncologist at U of C, he was becoming incapacitated with bone pain. (it was shocking and VERY scary how quickly the bone mets progressed to cause incapacition! -perhaps due to stress from the diagnosis??) That night, Feb 15th, at the advice of his new prostate specialist oncologist, he started the Casodex pills and had almost immediate relief from the bone pain. (so why didn't the 1st oncologist who diagnosed him tell him to start casodex asap!!!!! instead she said he had a "few weeks" to get other opinions if we wanted - GRRR!!!) More testing via U of C showed Gleason scores 7 (4 + 3) & 8 (4 +4), and he has the BRCA2 gene, and at Johns Hopkins (we went for 3rd opinion) not the AR-V7 (if I'm saying that last one correctly).

Initial treatment:

Casodex started Feb 15th, 1st Lupron shot on March 7th, and started Docetaxel chemo on March 28th - 6 sessions, 3 weeks apart.

(side effects were minimal, mainly exhaustion a for a couple days. To help minimize/prevent side effects, he took L-Glutamine and we iced his hands and feet via zip lock bags filled with ice to help prevent the neuropathy. Interesting that he started getting numbness on his heels where we weren't icing, so then we added an ice bag there too, which helped. Also did the artificial tears, every 10 - 15 minutes, to prevent tear duct problems, from the chemo pooling in his eyes) Last chemo was mid July and, once the exhaustion wore off, he started to feel really good. Well, except for the hot flashes, so added a 37.5mg Venlafaxine (75mg was too strong - it knocked him out).

His PSA went from 5.8 in mid January to 18.76 on March 7th, three weeks before starting chemo on March 28th, then to 3.25 the 1st day of chemo, thanks to almost 6 weeks of Casodex. Day of his last chemo, on July 11th, PSA dropped to 0.11. His last PSA test was Nov 9th (for 3rd Lupron shot), and was just slightly higher. I don't have the exact number handy, but I think it was something like 0.19.

About 3 months ago (late Sept) he started an exercise program and was looking forward to, hopefully, at least a couple years of progression free status - and being able to enjoy life again.

Late Nov/Early Dec (9-10 months after starting Casodex and 4-5 months after ending chemo) that ended maybe a month ago when he started getting pain in his butt which then radiated down to his foot. With no other symptoms of progression, he thought for sure it was sciatica caused from the exercise program. A week ago an MRI of his lumbar spine proved otherwise - tumor activity (osteoblasts) pressing on the nerves in his spine. We saw a neurosurgeon and a radiologist yesterday. The neurologist prescribed the 'Medpak' (think that's what people call it?) - methylprednisolone 4mg dosepak 21's, which he started today, and the radiologist mapped him and scheduled him for his first low radiation next week. This last week he's been in debilitating pain, so he moved from OTC meds to prescription meds:

2 Percocets (the oxy5-325's) every 4-6 hours, and 1 50mg diclofenac every 8 hours. This was working pretty well until this morning, so he's now adding tramadol for the break through pain. Wondering if all the walking around the huge hospital yesterday and all the sitting caused the pain progression today?

His oncologist mentioned getting him into a clinical trial of arbiterone (Zytiga) + Olaparib. Has anyone here tried this? Nalakrats mentioned soemthing about Dana Farber having a similar trial using nanotechnology, to get the drugs into the tumor vs 'hitting' the tumor, if I understand correctly.

Has anyone else with a similar profile been through this route?? Any words of wisdom?? TIA!!

[Hidden]

Not a doctor here, but will give you my opinion based on what you've said so far. If you have extensive mets and a low PSA, your PCa is probably doesn't have a lot of the hormone sensitive variety of cells. So in that case, ADT would not be effective or resistance develops quickly. You have the BRCA2 mutation which also fits in with the response you've had to treatment so far. BRCA2 is not responsive to ADT as far as I know.

My guess is that the chemo may have actually been working more effectively than the primary ADT, especially if he was feeling better then. You probably won't be able to rely on PSA numbers to tell you much since they are low. There are types of PCa cells that don't express the PSA. I doubt that chemotherapy was feeding the tumors in your spine, I think the opposite is probably true.

Castrate resistance to ADT and also resistance to Taxane chemotherapy can develop fairly quickly in BRCA mutated PCa. There is a targeted treatment available for BRCA mutated prostate cancer called a PARP inhibitor. Another option may be the use of platinum-based chemotherapy. I would also keep an eye on the liver, get some imaging to make sure no mets there and also watch the liver enzymes.

Talk all of this over with your doctor, hopefully a Medical Oncologist that specializes in prostate cancer. You really need one if you don't already have one. Good luck with your treatments and keep us posted please.

[JLS1 in reply to Hidden]

Hi Gregg, Thank you for your input. My husbands PSA did go much higher. I edited my post to show the PSA at 18.76 after 3 weeks on Casodex alone. Given by that time he no longer needed a cane, his PSA must have been much higher the day he started the Casodex, on Feb 15th. Wish I knew what it was then but I don't think it was tested for until he came in for his 1st Lupron shot on Mar 7th!! Here's an easier way to see:

Mid Jan 2017 test at first hospital: PSA at 5.8

Moved to U of C with prostate Oncology team on Feb 15, 2017:

Feb 15, 2017: PSA @ ??? started Casodex (by this time bone pain had excelerated quickly to requring a cane to walk)

Mar 7, 2017: PSA @ 18.76 after 3 weeks on Casodex - able to walk w/o cane. Got 1st Lupron shot.

Mar 28, 2017: PSA @ 3.25 after 6 weeks on Casodex & 3 weeks after 1st Lupron shot. Started chemo (Docetaxel)

April 18, 2017: PSA @ 0.59 three weeks after 1st chemo.

May 9, 2017: PSA @ 0.23 three weeks after 2nd chemo

May 30th, 2017: PSA @ 0.16 three weeks after 3rd chemo

June 20, 2017: PSA @ 0.12 three weeks after 4th chemo

Jul 11, 2017: PSA @ 0.11 three weeks after 5th chemo

Nov 10, 2017: PSA barely changed, think it was 0.19 or something like that. need to find report. 3rd Lupron shot given.

Late Nov/Early Dec - symptoms from bone tumor in lumbar spine begin (same area he had tumor activity when first diagnosed). Thought for sure it was sciatica, possibly caused by exercise program that he started a couple months earlier until MRI on Dec 29, 2017 showed tumor pressing on nerves in spine.

[Hidden in reply to JLS1]

What is your doctor suggesting for the next steps in treatment or diagnostic tests?

[JLS1 in reply to Hidden]

He has been out of town for the holidays, but sent an e-mail. We are meeting him next week to discuss "numerous" new treatments, including participating in the U of C clinical trial of Zytiga + Olaparib. It will be very interesting to hear what else he has in mind.

For ASAP pain relief, our oncologist recommended radiation: Low (safe) dose radiation treatment to begin next week, 10 doses, consecutively.

[Hidden in reply to JLS1]

You might know already, but Olaparib is a PARP inhibitor and it can be effective against BRCA 2 mutated prostate cancer so he could respond well to that.

Radiation is very effective for pain relief, so he will probably be doing much better after the treatments.

Sounds like you are going in a good direction. Let us know how everything works out.

[JLS1 in reply to Hidden]

I will post updates as they come. Thank you.

[JLS1 in reply to Hidden]

It would be great if all these new PARP inhibitor drugs prove to work well for mCRPC too:

curetoday.com/conferences/2...

"Three of these oral agents have been FDA-approved for specific indications in ovarian cancer: Lynparza (olaparib) in December, 2014, Rubraca (rucaparib) in December, 2016, and Zejula (niraparib) in March, 2017. These drugs continue to be the topic of investigation for expanded use in ovarian cancer, and Moroney mentioned two other PARP inhibitors in development: veliparib and talazoparib."

[Hidden in reply to JLS1]

Here's a quote from an article regarding s study of PARP inhibitors to treat mCRPC with various genetic mutations:

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

METHODS

We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.

RESULTS

Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes — including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2 — in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.

CONCLUSIONS

Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.

[JLS1 in reply to Hidden]

Thank you so much. Yes, I did see this the other day, and it's encouraging. Also encouraged by the specialists we've been in contact with very recently saying many new 'weapons' against PC are in the pipeline. Fingers crossed. We need to ERADICATE this PC beast!!

[EdBar in reply to Hidden]

Thanks Greg 57 - I have a CHEK2 mutation and filed this info away, in case I need it so I can present to my onco.

Ed

[Hidden in reply to EdBar]

I was just reading about CHEK2. It's rare and I had never heard of it until I read the article. I think looking ahead at where treatments are going, reasearchers will need to figure out the mechanisms of resistance and find the proverbial "chink in the armor". The evolutionary timescale of the cancer is very short so it evolves quickly with mutations that have a survival advantage dominating. It's hard to stay ahead of them.

[EdBar in reply to Hidden]

I had genetictesting done thru Dr. Sartor, Snuffysreplacement in my case. They did it for free as part of research they are doing at Tulane with a company called Invitae.They also discovered another rare mutation called NBN - Nijmegen Breakage Syndrome. They are now offering to test my kids as well so they know if they also have these mutations.

Ed

[podsart in reply to Hidden]

Gregg57

I just wanted to note that I have observed your kind and informative responses, which seem to appear all over the place. I think you should be applauded for your consistent help and sensitively given advice and support.

[Hidden in reply to podsart]

Thanks!

[JLS1 in reply to podsart]

Here's another encouraging article I just found:

Role of PARP Inhibitors Clarified in Prostate Cancer

Ariela Katz

Published Online: May 22,2017

targetedonc.com/publication...

Our understanding of the genomic landscape of metastatic castration-resistant prostate cancer (CRPC) has been rapidly progressing, with new clinical data emerging to clarify and, in many cases, support the use of poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of these patients.

“PARP is an important mediator of DNA repair as the DNA strand breaks,” explained Celestia S. Higano, MD, during a presentation at the New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies. “And so, when we have a patient who has an underlying DNA repair problem and we inhibit PARP, we can end up with a situation where there is no DNA repair, leading to cell death.”

Study results published in Cell in 2015 showed that genomic testing of bone or soft tissue biopsies from patients with metastatic CRPC proved that 23% of metastatic CRPC tumors harbor DNA repair alterations. Aberrations of the androgen receptor (AR), ETS fusions, TP53 mutations, and PTEN mutations were frequently observed (40%-60% of cases), with TP53 and AR alterations enriched in metastatic CRPC compared with primary prostate cancer.1

Additionally, aberrations of BRCA1/2 and ATM genes were observed at substantially higher frequencies (19.3% overall) compared with those in primary prostate cancers. The study found that 89% of affected individuals harbored a clinically actionable DNA aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with pathogenic germline alterations that are actionable. The study also determined that the frequency of DNA repair alterations increases with disease progression.

In a phase II study of olaparib (Lynparza), a PARP inhibitor, treating patients with metastatic CRPC and DNA repair defects, the drug was proven to lead to high response rates in this patient population. The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel (Taxotere), abiraterone acetate (Zytiga), enzalutamide (Xtandi), or cabazitaxel (Jevtana). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33%) had a response to the treatment with olaparib, with 12 receiving the treatment for more than 6 months.2

The study concluded that the presence of defects in DNA repair genes found in biopsies of metastatic tumors was associated with a high response rate to olaparib in 14 of 16 patients, including all 7 with loss of BRCA2. “They didn’t really know this until after the study, but 14 out of the 16 responders had DNA repair alterations. This was a pretty small study, but it has prompted a lot of interest in researching PARP inhibitors in prostate cancers,” commented Higano, professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.

DNA repair alterations are present in approximately 25% to 30% of cases of metastatic CRPC. These include BRCA1/2, ATM, Fanconi’s anemia, CHEK2, and other gene alterations. Higano stressed that there are 2 ways a patient can have these alterations: either in tumor DNA, which is observed in about 25% of patients, or in the germline setting, which is observed in approximately 12% of patients.

If these DNA repair alterations are present after treatment with abiraterone, docetaxel, or enzalutamide, there is a higher response rate to olaparib. However, 1 challenge is the lack of data regarding the overall survival (OS) benefit for patients with CRPC, although olaparib has a breakthrough designation from the FDA based on a study published in the New England Journal of Medicine.2 “It’s not that difficult to get olaparib for your patients,” Higano commented.

Numerous other PARP inhibitors are also in development, including veliparib, niraparib (Zejula), rucaparib (Rubraca), and talazoparib. Additionally, there are many combinations studies with PARP inhibitors, and so patients who do not have a DNA repair alteration are not necessarily excluded from the potential benefits of PARP inhibitors.

One such combination study is the phase I KEYNOTE-365 trial, which is investigating the safety and efficacy of combination therapies with pembrolizumab (Keytruda) in patients with metastatic CRPC (NCT02861573). There will be 3 cohorts in this study, each with approximately 70 participants: cohort A will receive pembrolizumab combined with olaparib, cohort B will receive pembrolizumab combined with docetaxel and prednisone, and cohort C will receive pembrolizumab combined with enzalutamide.

A phase II randomized, open-label, multicenter trial is also assessing the efficacy abiraterone and prednisone with or without added olaparib in comparison with olaparib monotherapy (NCT03012321). Patients with metastatic CRPC that have an ATM, BRCA1, or BRCA2 mutation will be randomized to 1 of 3 arms.

There are some challenges facing the development of PARP inhibitors. One of the problems is that it takes a long time, often 2 to 6 weeks, for the results of tumor biopsies and germline tests to be processed for eligibility for biomarker-driven trials. Despite these challenges, several studies of PARP inhibitors driven by DNA repair biomarkers are ongoing. In the phase III, randomized TRITON3 study, investigators will be assessing how patients with metastatic CRPC and evidence of a homologous recombination gene deficiency respond to treatment with rucaparib verses treatment with a physician’s choice of abiraterone, enzalutamide, or docetaxel (NCT02975934). This study is currently enrolling participants who have a deleterious mutation in the BRCA1/2 or ATM gene.

“The thing that makes this trial stand out from all the others is that most of the other trials require patients to have failed docetaxel, whereas this rucaparib trial allows patients to be treated with rucaparib or a choice of abiraterone, enzalutamide, or docetaxel. In terms of patient accrual, patients are allowed to cross over to the rucaparib arm once they fail in the control arm,” Higano said.

In the phase II Galahad study of niraparib, investigators are assessing the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic CRPC and DNA repair anomalies (NCT02854436). The trial is looking at overall response rate as its primary endpoint, with OS and time to prostate-specific antigen progression included as secondary endpoints.

“I think it’s become increasingly apparent that we need a thorough family history of cancer that might point to patients with DNA repair defects,” said Higano. As genomic testing for directing targeted therapies becomes more integrated into the standard of care for patients with CRPC and PARP inhibitors show more durable responses in clinical trials, these agents will become increasingly available.

References:

Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer [erratum appears in Cell. 2015;162(2):454]. Cell. 2015;161(5):1215-1228. doi: 10.1016/ j.cell.2015.05.001.

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate can- cer. N Engl J Med. 2015;373(18):1697-1708. doi: 10.1056/NEJMoa1506859.

[V10fanatic in reply to JLS1]

You just gave me a whole week of research to do-

[Sisira in reply to podsart]

Yes, gregg57 deserves our appreciation in a great deal.

Sisira

[Roland632017]

Hi JLS1

I am not an expert.

I am also been opposed by this community as well as a very qualified doctor very closely related but the last few days is willing to play along as an observer.

I have stopped using doxycycline/Vitamin since I encountered pain then had to undergo a cystoscopy to now added left ureteric stent.

Through my journey I have indicated as was lucky and was rewarded/repaid by my kind gesture back in January 17. In January I withdrew A$10000 and from that A$4000 was donated to the Council for Deaf & Blind.

I am making this a crusade as clearly all of us are deaf and blind as we only wanted to hear/see what we want to see.

Now coming to the cancer pains that you said your husband had to endure.

Through my journey so far I am pain free ( even Dr Richard Wassersug was surprised )

On top of this I am on/off medication due to haematuria probably ( combining physical over exertion & haemorrhagic cyctisis of bladder tumour)

But for a few days on my intense treatment I felt for the first time pain surrounding my back/spine region and after 3-4 days it disappeared, I think I had hit the bone cancer hard.

My last CT scan the Radiologist reports every things stable and even missed out on my bone lesion,

I had to get my local physician to contact him to reanalysed, he was quite adamant the bone lesion wasn't showing up up chances his mind and reports no change as from last CT scan 18 December 17.

What ever happens I think time line is important so I would execute another CT & Bone Scan at the end of this month.

So for the moment I am using green tea which has a ph 9 to maintain my Urine & Saliva ph 7.5 and above.

Since my urine (visible observation no blood) urine test confirmed haematuria I have resumed my other medication.

Roland

[vandy69]

Good Morning JLS1,

I can only comment on the PARP inhibitor, Lynparza. I took it for almost 1 year as it was prescribed by Dr. Charles Myers after a Guardant360 liquid biopsy revealed an ATM defect (please see my bio for treatment history).

It seemed to control PCa, but I was taking many drugs and also receiving proton beam radiation. In clinical trials, it was effective for about 9 months.

Check your husband's insurance coverage because Lynparza retails for about $10,000/month, as does Zytiga.

No side effects that I recall.

Best wishes. Never Give In.

Mark, Atlanta

[JLS1 in reply to vandy69]

Mark, if he gets this via a clinical trial, aren't all costs covered, including all the tests prior starting the drugs? I'd think they'd want to give him a thorough work up - blood tests, MRI's, bone scans, etc to see where the cancer is and measure it. Will find out from the oncologist later this week. He was out of town over the holidays, returning this week.

[vandy69 in reply to JLS1]

Hi JLS1,

I have not yet been in a clinical trial, but I would think that all drug and scan costs would be covered by the trial managers.

I had a friend in a trial at NIH and they even paid for his travel expenses from Atlanta!

Early in my treatment I took Zytiga plus Prednisone for about 18 months and more recently took Lynparza. Could be a strong combo and if a trial, you want your husband in the arm receiving both and not placebos.

Hope he does well!

Best wishes. Never Give In.

Mark, Atlanta

[JLS1 in reply to vandy69]

Thank you Mark. Pretty sure the oncologist said he'd get both. He has the BRCA2:

clinicaltrials.uccrc.org/Di...

A Randomized Phase II Trial of Abiraterone, Olaparib, or Abiraterone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects

This is a biomarker preselected, randomized, open-label, multicenter, phase II study in men with metastatic castration resistant prostate cancer (mCRPC). Patients with tumors that have ATM, BRCA1 and/or BRCA2 mutations/deletions/loss of heterozygosity will be randomized in a 1:1:1 fashion to each arm. Patients with mutations in noncanonical DNA repair genes including FANCA, PALB2, RAD51, ERCC3, MRE11, NBN, MLH3, CDK12, CHEK2, HDAC2, ATR, PMS2, GEN1, MSH2, MSH6, BRIP1, or FAM175A defects will be assigned to Arm IV with single agent olaparib.

[pjoshea13]

The thread title may be a little misleading.

Sadly, all PCa monotherapies induce resistance - sometimes quite quickly. Such treatments select for a population that is much harder to kill & often more aggressive. Ultimately, successful PCa treatments will come with inhibitors of resistance.

In the new study, as I understand the following extract, BCa bone mets resist chemo via JAG1 upregulation, & this can be avoided via use of a JAG1 antibody.

"Major finding: Chemotherapy induces JAG1 expression in osteoblasts, promoting chemoresistance in bone metastases. Concept: A JAG1 antibody sensitizes breast cancer bone metastases to chemotherapy with minimal toxicity. Impact: JAG1 may be a therapeutic target to prevent or reduce bone ..."

-Patrick

[Hidden in reply to pjoshea13]

Thanks, I agree with the misleading nature of some of these articles. You know that saying: "whatever doesn't kill me makes me stronger". No treatment will kill all the cancer cells and whatever survives will have an advantage. Survival of the fittest. The big problem is that on an evolutionary timescale, we are not fighting on a level playing field. Generations in the world of cancer cells are measured in hours. We are all just trying to get as much time as we can.

[pjoshea13 in reply to Hidden]

Gregg,

One need not look at an actuarial table to assess how many years we might have reasonably enjoyed, were it not for PCa. For many of us, most non-curative therapies come up short.

I have two approaches. [1] Delay as long as possible treatments that are merely palliative - why hasten their failure? [2] Combine as many therapies that may extend the effectiveness of the primary one. I include Metformin, Avodart, Statins, etc, etc; not just the big guns.

-Patrick

[Lunbo]

Have had PCa for 16 years and have not yet been on chemo except casodex then to Lupron and then adding Zytiga with Prednison which I was on for 5 years now on Xtandi. Why would you have to enter a clinical trial for Zytiga?

[JLS1 in reply to Lunbo]

It's for Olaparib and they do it along with the Zytiga