斯科特T.Gagawa,MD,Weill Cornell Medicine的医学和泌尿科教授,以及在纽约 - 长老康奈尔医疗中心主治医生,解释了前列腺癌中前列腺特异性膜抗原(PSMA)的益处和路障治疗。

这是与Tagawa博士的三部分对话中的第二个。手表第一部分本探讨了前列腺癌治疗的最新发展。

DocWire新闻:PSMA已成为前列腺癌感兴趣的目标。您可以将PSMA讨论为目标,以及您对扩展治疗方案的潜力的思考吗?

斯科特比瓦,MD:PSMA很好,因为它几乎总是在前列腺癌的情况下,在具有高等级,转移和荷尔蒙治疗的前列腺癌的环境中具有更大程度的。特别是在转移性,或经常性的人口,特别是在治疗的人群中,这是一个感兴趣的目标。我会说这是一个临床验证的目标,因为PSMA成像代理实际上已经超过二十年前批准了。发生了什么,我认为技术的改进是倾向于很快批准至少一个,如果不是多个诊断成像代理,PSMA宠物代理商我认为,即将推出,并与PSMA靶向治疗剂并行。

我会把这些纳入三个一般课程。有抗体药物缀合物等药物,或小分子毒素缀合物;这是我们希望改善的一类。There are immune ways of targeting, whether that’s a CAR T cell, or bi-specific, those are in development, generally speaking in phase I. The early data shows that there’s toxicity, as expected, but they look to be a subset that can have a deep response, and we’re waiting to see how durable that can be. The furthest along, and that was partly because, based upon what technology was available a couple of decades ago when we first started in the clinic, is targeted radionuclide therapy. Using PSMA as a self-service target, having some sort of a targeting agent, generally speaking either a small molecule or an antibody, and attaching a radioactive particle, most commonly a beta emitter such as lutetium-177. Also, different alpha emitters have been used, either as part of “standard of care,” in countries that have laws that say anyone that doesn’t have anything else can get one of these, or as part of clinical trials, and clinical trials are quite young for the alphas, but now maturing for the betas.

今年年初在ASCO中,我们看到了随机期II试验的初步结果,比较了PSMA-617的卢比卢比,这是一家经过几家不同公司的β放射性标记的小分子,目前居住在AAA Novartis,头部到头卡基特克斯。基于PSMA和FDG宠物成像的选定患者,以便符合其符合条件并非所有的方式,更多的PSA减少至少50%,与化疗相比,放射性配体疗法。偏移毒性通常更多地用于化疗,但不同的毒性。在这是一个阶段,我们将审判视为愿景,该届愿景已完成招生。因此,我们怀疑我们将在2021年初拥有一些数据,这可能导致这种类型的代理人批准。

这是一种类似于具有含含卢和放射性标记的生长学素类似物的神经内分泌GI癌症和胰腺癌的类似类型的高跟鞋。这将是前列腺癌的第一个放射性标记的治疗剂。我们许多人怀疑这将是一个积极的审判,可以导致第一批准PSMA目标代理人。We have radium, and we’ve had other bone-targeting beta emitters, but radium, the key with that is it’s an alpha and it has an overall survival advantage, but it’s not directly tumor targeting it’s bone targeting, hydroxyapatite, whereas PSMA is tumor targeting, as well as the other areas in the body that express PSMA, such as the salivary and lacrimal glands, the small intestine, and part of the kidney.

DocWire新闻:你认为缺陷或潜在的障碍是瞄准PSMA的缺点吗?

斯科特比瓦,MD:所以一个,我猜这不是PSMA独有的,但随时我们有一个非常特定的目标,包括PSMA,它并不总是在那里。因此,有一些肿瘤是psma阴性。Generally speaking PSMA has a link to the AR, androgen receptor, pathway, so in the tumor types that we might call neuroendocrine small cell, or there’s various names for that, but have loss of AR, those are the most likely to lose PSMA, as well. So, an entire tumor burden patient might be PSMA negative or low. There’s also some heterogeneity. So, most of the time when we do an image we see all the tumors light up fairly brightly, but we know from studies that have looked at tissue is that not every single cell within a tumor might have PSMA on it, and that there are different levels of PSMA.

这是一种方式是组合。另一种方式是与具有较长路径长度的β发射器的交叉轮胎效果。这是任何PSMA靶向治疗的缺点,以及任何治疗,我认为,这是一个代理人,目标可能只有部分或根本没有,取决于患者。One of the nicer things about, let’s call it the theranostic platform, meaning having some sort of imaging of the target, followed by treatment of the target, some people are strict enough to say that agent has to be the same agent, but let’s say, loosely, some sort of PSMA imaging with PSMA-targeted therapy, at least we’ll get an idea of those who are completely negative. Then, may also have an idea, based upon level of uptake, some hint at heterogeneity that is there.

I think that will be a nice pair, and I think that, hopefully, is a nice problem to have once we have the available drugs, and figure out do we not use this therapy at all, or do we pair it with another drug that’s either going to alter the targets i.e. make more PSMA expression, and/or amplify the results, such as an agent that would lead to radiosensitization, if we’re using it with a radioactive particle.