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Andrei Iagaru: Thank you, Jeremie and, again, to the organizers for going beyond PSMA. And also could not have a better introduction to other hammers than this discussion. So I hope I'm not going to be biased-- like if you have a hammer, everything looks like a nail-- but rather show you that there are complementary ways of finding prostate cancer and hopefully, in the end, treat it as well.

Rob and Tanya afterwards will talk about other targets. So I'm not going to spend too much on that other than to show you this small molecule, FSPG. And tribute to Anand Srinivasan, the person who discovered this molecule way, way back, this glutamate analog. And perhaps it's a super FDG. My colleague Erik Mittra did this work in prostate cancer patients. So that's the expression of glutamate transporter in a patient with prostate cancer. Corinne Beinat is working on a second generation that has more specificity and can be used for therapy as well.

Before I go to GRPR, I want to really mention Professor Helmut Maecke, who, those who are familiar with the work, is behind many, if not most, of the molecules that exist in this space of GRPR. And he had a connection to LA as well-- although arguably you can say on the wrong side of town-- at USC, where he spent some time in Professor Walter Wolf's radiopharmacy department.

So what are GRPRs? Gastrin-releasing peptide receptors are overexpressed in a variety of cancer types, including prostate cancer, but also are involved with many biological processes, from those in the neural space to the GI space. But importantly for what we're talking about, it's the metastatic potential of cancer. So cancers that are more aggressive and tend to metastasize overexpress GRPR.

Let's just put something to rest. In GRPR, we're talking about imaging and treating with antagonists. Agonists have been tried as the first line, but they are so potent that even in the very small dosages given for diagnostic purposes, there are reports of side effects. So people who receive these agonists of GRPR experience GI symptoms. And it’s reported in the therapy versions that there were severe side effects from the small peptide that was labeled for those purposes.

This is the best paper to show that the agonists do not do as well as antagonists. The bone scan was there for them, but I think he left. But at the top row is the antagonist, where you see some lesions in this patient with prostate cancer. The bottom is agonist. None of those are visible.

So of course, we send antagonists. You don't need an activated receptor. So you have a higher chance of finding where these lesions are. And if you're into chemistry and how these molecules are derived, majority of them are derived on the same motif. As you can see at the bottom, there are still derivatives, those that have been more widely used.

So we started using one of these molecules in 2015, the same time as we started using PSMA-11, and the biodistribution of the two agents could not be more different. Of course, you have the pancreas uptake with GRPR, but that's a radiosensitive organ. And like a true antagonist, the signal washes out from the pancreas, as I'm going to show you later.

So where in the course of prostate cancer should we use this? I understand why pharma needs to go at the very end to get overall survival data and other things of that nature. But if we want to make an impact in survival, we need to go to earlier stages of disease, as was mentioned by the previous speakers.

And let me show you what we've done with GRPR from even men without a diagnosis of prostate cancer. So I don't see Steve in the room. He was here yesterday, talking about, what role can MR have? Well, there's no better tool than PET/MR, if you have PET/MR, in this early stage, where you have men with equivocal or negative multiparametric MRI. And instead of putting them on surveillance or repeated biopsies, you add a PET signal to try to find the cancer.

And this is what we've shown in this pilot study from several years ago now. So if you add either PSMA or RM2 PET to MRI in patients with negative or equivocal multiparametric MR, you are able to help the urologists biopsy the area that has cancer, which in this case was in the anterior aspect of the prostate, an area that's difficult to accurately identify cancer. And here, the green dots are showing the blind biopsy needle tracks that missed the cancer perfectly.

Now, also in the early prostate cancer space, in intermediate or low risk, you can do high-intensity focused ultrasound or TULSA. Those are therapies that are widely used here at UCLA. The problem is, if you only know about the cancer from MRI and you don't know about the presence of the others, you're heating up one area where you have the cancer and you can have disease progression elsewhere.

So we wanted to show in this trial that adding RM2 and PSMA to MRI, you can identify additional cancers so that patients should not be treated with HIFU TULSA, and also that you can eliminate the need for a biopsy six months after treatment. And I think we're quite successful in that as well.

In the high-risk prostate cancer patients, prior to prostatectomy, we've shown that RM2 can guide the signal. And just like at other institutions, we have access to the histology slides marked in ink by the pathologist. And the signal on PET correlates very nicely with where the cancer is located. And in selected cases, the primary may show the same level of uptake, but there are some lymph nodes that I would argue are much easier seen with the GRPR at the bottom versus the PSMA on the top row. Not every patient will look like this, but there will be some.

And then you have cases where the GRPR PET finds the prostate cancer and PSMA does not. So even under the most optimistic scenario that 90% of prostate cancer overexpress PSMA, not 100% of those-- 90% of patients will have 100% lesions that are PSMA-positive. So that heterogeneity exists. And we can find those other receptors by using additional radiopharmaceuticals.

Our largest experience is at biochemical recurrence, where we ran a phase I and phase II, and then a phase II/III trial. This was designed in 2013. There was no widely available PSMA, so eligibility did not include that. The pilot study compared RM2 with PSMA-11, and several patients had more lesions on RM2 than on PSMA-11.

An interesting finding in the phase II component of this was that the PSMA velocity was definitely higher in patients with RM2-positive GRPR versus those with negative scans. So perhaps those that are false negative are cancers that are more indolent, that maybe should be left alone, and we shouldn't be too aggressive to treat them. We shouldn't overtreat. And the phase II/III trial was published in Lancet Oncology last year. And per quartile, the PET positivity was similar to what has been reported in the PSMA literature.

One example that is illustrative, and we all-- everybody who used GRPR has anecdotal cases where there is significantly more activity on GRPR than on PSMA. So if you think of this as a theranostics tool, I think I can make a strong argument that you should use the lutetium or actinium version-labeled of the GRPR and not the PSMA.

The first patient treated worldwide was in Santiago by Vasko Kramer and his colleagues. And this work is important because it shows that the pancreas washes out while the activity in metastatic lesions is retained up to, in this case, 168 hours. And same results in the group from Rostock, showing that the pancreas is seen there by one hour but washes out, while the lesions retain the activity for several days after.

Another group that we looked at, we looked at PSMA R2 versus NeoB. PSMA R2 was mentioned in one of the earlier talks as having less salivary gland activity. Unfortunately, it also has less prostate cancer lesions activity. So perhaps it can be salvaged as a molecule for alpha-label therapy. But for diagnostic purposes, as you can see in this case, it was not acting as intended. So we saw more lesions with the NeoB GRPR tracer than we saw with PSMA R2.

And we feel that at this point the field is at a time point where we need to have unified criteria. And we took the PROMISE criteria for PSMA, and we applied them in a way that we think can be reproduced regardless of what PET pharmaceutical we use. And we used an atlas of biodistribution to identify organs that can be used as reference.

So these are the side by side, the PROMISE and the modified PROMISE for GRPR, and you can see what we defined as classes that can have reproducible uptake. And we're seeing that everything above GI tract and definitely above pancreas should be translated into a potentially good theranostics candidate. And the agreement ranged from substantial to almost perfect for three blinded readers who evaluated this set of criteria.

As far as future directions, there are groups like Francois Benard's, who works on reducing the pancreatic uptake. But again, that reduces the tumor uptake as well. So I would advise against that. There are the Copper-64 and -67 compounds SAR-Bombesin that were shown to, in selected patients, work better than gallium-PSMA-11. And there's also the AMTG derivative from M2 that has been shown to have perhaps better biodistribution and has been labeled with terbium as well as with lead-212.

So before I get to conclusions, this is something that has recently been accepted in JNM, a collaboration between academic centers doing GRPR and industry working on GRPR. And these are our recommendations for how to use GRPR in clinical trials going forward, including criteria for patient selection for treatment.

So to conclude then with my wish list here, we've shown great progress in this space of GRPR, and there are now more and more companies and groups reproducing our early results. And so I would hope that it will not take us another decade to get at least one pair of these GRPR radiopharmaceuticals approved by the FDA or whatever other authorities.

And with that, I want to thank my colleagues who worked on this. And I also want to acknowledge many of the people worldwide who worked on development of GRPR radiopharmaceuticals, particularly Rosalba Mansi, whose initials are in the RM2. She was working in the lab with Professor Maecke when this was discovered. And with that, thank you so much.