NEPC Targeting

[Javelin18]

Some responses to my earlier posts suggested I might want to think twice about persueing Lu-PSMA therapy, since it might create an opportunity for NEPC repopulation. Since I already have aggressive cancer, it seemed that I should treat it, without worrying that it might lead to aggressive cancer.

I’m always looking at the next possible therapy so I started looking at CAR-T and BITE antibody targets PSMA and PSCA. When I saw that PSCA is more widely expressed than PSMA , I began to wonder if it would also be a target for NEPC. This paper indicates that it has potential for that.

pubmed.ncbi.nlm.nih.gov/330...

Here’s a snippet from the abstract

Using the typical androgen deprivation therapy, most tumors will progress to CRPC, as well as develop into neuroendocrine prostate cancer (NEPC) characterized by the expression of neuroendocrine markers such as enolase 2 (NSE). Our study was aimed at investigating the expressions of PSCA and NSE and the relationship between the two markers, as well as the correlation between the PSCA and NSE expressions and the clinicopathological parameters in prostate cancer specimens from 118 patients by using immunohistochemistry. Our results demonstrated that the PSCA and NSE protein expressions did not correlate with the prostate cancer patients' age or the hormone therapy but showed a significant correlation with the pathological tumor stage of prostate cancer, the Gleason score, and the presence of metastasis. There is a positive association between PSCA and NSE but a negative one between the prostate-specific antigen (PSA) and PSCA or between PSA and NSE. High PSCA and NSE expressions correlated with a poor prognosis in prostate cancer patients. PSCA may play an important role in the progression of neuroendocrine prostate cancer (NEPC).

[Tall_Allen]

NEPC is just one type of PCa that does not express PSMA or PSA. Unless you have been specifically diagnosed (via IHC) with NEPC, this is not an appropriate target.

[Javelin18 in reply to Tall_Allen]

PSCA is expressed in Adenocarcinoma and even placental tissue. It seems to be an appropriate target for all forms of PCa and is currently under trial in BITE and CAR-T.

[Tall_Allen in reply to Javelin18]

Yes, I know. I've talked to Tanya Dorff about those trials. But I was asking if you've been diagnosed with NEPC - or why the concern?

[Javelin18 in reply to Tall_Allen]

My concern arose from some of your previous posts that said Lu-PSMA therapy might lead to repopulation of previous adenocarcinoma sites with NEPC. I value your breadth of knowledge, so I thought I should try to understand options if that occurred.

[Javelin18 in reply to Javelin18]

It’s not really a concern. My main goal is to have enough knowledge to have meaningful conversations with my care team.

[Tall_Allen in reply to Javelin18]

Resistant types are not just NEPC, it's all prostate cancer that is not PSMA-avid, which is 5% across all metastatic men but may be higher among a heavily-treated population. The problem with prostate cancer stem cells is that while they occur in most tumors, most of the prostate cancer tumor consists of normal prostate cancer with very low concentration of cancer stem cells. By targeting them with BiTE or CAR-T, the hope is that it will diminish the creation of new PCa cells from them. But because of the low concentration, it may not have the effectiveness that a target that is widely expressed may have. Dr Dorff believes an effect called "antigen spreading" may occur, whereby the activated T cells get keyed in to attack cancer cells that do not express PSCA (especially when combined with checkpoint inhibition). These are the questions that only clinical trials can determine.

[Javelin18 in reply to Tall_Allen]

Thanks for that information. I had been wondering if antigen spreading might occur with PSMA targeting also.

I expect that I may exhaust the usefulness of PSMA, with my Lu-PSMA treatment, and would need a different target. I think that my current treatment may disqualify me from PSMA CAR-T and BITE trials in the future.

Seeing that PSCA occurs in NEPC, while PSMA doesn’t, makes it a more appealing target.

[LearnAll]

I would like to see a definitive diagnosis of Neuroendocrine Variant before anything else is suggested. How to rule out NEPC...(1) Check 4 NEPC blood biomarkers. Chromogranin A, Neuron Specific Enolase , Synaptophysin and Lactate Dehydrogenase.

(2) Plain X ray of all bone ,to be read by an experienced Radiologist to see if there are any Osteo lytic bone lesions.alternatively , you can get a CT with and without contract to see osteolytic lesions. and (3) Biopsy to see NE cells in prostate and/or Met tissue.

If you find out that you Do Not have NEPC, then you can go the path of aggressively treating your "aggressive" PCa.

[Javelin18 in reply to LearnAll]

Thanks LearnAll. I am aggressively treating my PCa. Since my diagnosis the first week of January last year, I’ve been treated with Degerelix, Lupron, Docetaxel, SBRT of the primary tumor, aberaterone and now Lu-PSMA. I’ve used up most SOC treatments, and want to have an idea of where to turn next, should biochemical relapse occur at the end of my Lu-PSMA treatment in June.

Participating in some trials excludes others, so I want to optimize my choice of trials. I asked my MO to check Chromogranin A during my next blood draw. I’m not assuming that I have NEPC, but like the idea of PSCA as a target instead of PSMA. Since I will have already targeted PSMA with Lu, I’m looking into the potential benefits of PSCA. When I consulted with Dr Dorff last February, she told her trial was targeting PSCA, so I wanted to learn more about it.

I shared what I learned thinking that others might find it useful

[Seasid]

Are you getting something to strengthen your bones? What is it and how often? If you are getting lutetium psma treatment I would think that you are receiving something. It wasn't in your profile. I didn't read your past posts yet.

[Javelin18 in reply to Seasid]

I’m getting denosumab (Xgeva) injections. I think it is every two months, but I would need to dig through my past records to find the schedule. To ensure that doesn’t lower my serum calcium, I take daily calcium supplements. Blood tests show my calcium to be in the middle of the normal range.

[Javelin18]

Thanks,

The Lu -PSMA treatment seems to be going well from the clinical signs. Much less pain, and better energy. PSA and ALP both shout up after the first treatment. Got the second treatment December 17.? I will have a blood draw this Friday.

I got used to dropping PSA two weeks after docetaxel, but Lu has a half life of seven days. I think this keeps PSA and ALP higher longer.

I am having persistent nausea that I need to discuss with my MO.

[Javelin18]

I’m thinking that after six cycles of Lu-PSMA I won’t have any PSMA avid cancer left. Any trial drug would need to target a different antigen.

[TeleGuy in reply to Javelin18]

I also thank you for opening up this interesting topic!

I don’t think you should assume that six cycles of Lu-PSMA will eliminate all PSMA-positive cancer. Mine is starting to come back again 18 months after five Lu-PSMA cycles, and it is PSMA avid on scans.

[Javelin18 in reply to TeleGuy]

Thanks, that’s interesting information.

[Bigm789]

Is PSCA a marker for localized PCa what is the G score range indicated, Is Invitae genetic somatic and germline testing indicated is you have no BRCA + genes?Would this be a blood test available along with PSA

[Javelin18 in reply to Bigm789]

PSCA is another prostate cell surface antigen, like PSMA. It occurs on all prostate cells , including cancerous ones. T cells can be genetically modified to recognize it as something foreign snd attack the cells (CAR-T). It can also be targeted with a Bispecific Antigen ( BITE). BITEs are molecules that attach to the antigen and have an attachment site in the other end for T cells. CAR-T and BITE are two cutting edge therapies that use the immune system to kill cancer. There are Phase 1-2 trials for BITE and CAR-T underway that use PSMA or PSCA antigens.

I hadn’t thought about wether they circulate in the blood, and could be used as a test. I don’t know why PSA is in circulation.

[CAMPSOUPS]

Hey Jav,You haven't been here long and I just want to thank you for your research and posts. You with your inquisitive brain inspire the other "brains" here to get involved in these threads and it becomes very instructive. Thanks again.

[Javelin18 in reply to CAMPSOUPS]

Thank you. I’m glad I’m helping to inspire some good discussions. They help me learn too. I had been doing research since last January with the help of my brother, but I’m glad to be doing it inside a larger well informed community.

[Scout4answers]

I want to echo Campsoups Thank You! While most of what you wrote is currently over my head, I gather more understanding as we roll down the hill. This forum is a godsend with so many minds trying to figure out a solution to our common problem.

[Cooolone]

I've gained an interest in the PSCA testing after learning about the CAR-T trials. My outside the box Peritoneal Presentation of my PCa always has me watching the fringes of new or upcoming detection and treatment. Just keeping an eye on the road ahead for what may eventually come (progression).

Thanks for posting!

[Javelin18 in reply to Cooolone]

Your welcome. This reminds to dig into what sort of scans for PSCA exist. My recollection is that there are PSCA PET scans, but I need to confirm that. Let us know if you find information on this.

[Javelin18]

I searched for PSCA PET imaging. All I could find was a study at UCLA imaging prostate tumors grafted into mice (xenograft). It looked promising, but the study was done in 2014. I’ll ask at my next appointment about it.

I may also message Dr Dorff at City of Hope about it. One of her treatment trials targets PSCA, so it would be helpful to be able to image it.

[NickJoy]

I asked my husband's oncologist about this trial and although he thought the trial was very interesting he was unsure if the neuroendocrine prostate cells could be targeted using PSCA - I guess you could ask Dr Dorff directly if they would be or could possibly be. I would love to know what she thinks. Best of luck.