I guess I'm hoping for it to be a new treatment on the way, as Tall Allen writes in his blogpost from December 2019:
"Uwe Haberkorn and researchers at the University of Heidelberg have synthesized a FAP inhibitor (FAPI) that seems to inhibit production of CAFs specifically and thoroughly. Not only does it inhibit progression in mouse models, but it seems to "fix" the problems associated with the cancer stromal compartment - imperviousness to immunotherapies and angiogenesis inhibitors. They are fine-tuning the ligand to be more sensitive and specific, and to last long enough in clinical use for theranostic applications."
Thankful for any insights! And yes, I have e-mailed University of Heidelberg (since my fathers diagnosis I'm not shy of stupid questions to professors and doctors anymore) but not gotten a reply.
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It's at least 5 years off as a therapy; there's a trial as a diagnostic at UCLA. Many drug companies are investing in it. I think it will ultimately be used as part of a combination - attacking both the cancer and its protective stromal compartment.
Dr. Sam Denmeade (Johns Hopkins) - of BAT fame - has co-authored papers on fibroblast activation protein (FAP) going back to 2009, included one published fairly recently.
Here is the Discusion section of that paper, which you might find interesting. Denmeade has been known to respond to emails.
"Discussion
"Therapeutic strategies targeting FAP
A multitude of strategies have been developed since FAP’s initial discovery in an attempt to exploit its restricted expression pattern and unique substrate specificity for clinical benefit. These approaches range from diagnostic and prognostic applications as discussed above to imaging and therapeutic targeting using a diverse series of modalities, several which have been evaluated clinically with mixed success. The therapeutic approaches generally fall into one of two categories – those designed to kill FAP+ cells (e.g., prodrugs, vaccines or immunotherapies) or those relying on inhibition of FAP enzymatic activity (e.g., small molecules). The first of these to be tested clinically was sibrotuzumab, a humanized monoclonal anti-FAP antibody based on the F19 antibody that was initially used to discover and characterize FAP expression [30,41,111,112]. Though sibrotuzumab was ineffective against metastatic lung and colorectal cancers in Phase I and II studies, it was well-tolerated and demonstrated tumor targeting [111,112]. The Phase I trial utilized Iodine-131 (131I)-radiolabeled sibrotuzumab, whereas the Phase II study evaluated unlabeled antibody for antitumor efficacy. As sibrotuzumab does not inhibit FAP enzymatic activity and was not optimized for antibody-dependent cellular cytotoxicity (ADCC), the lack of efficacy is not entirely unanticipated. Revisiting this space with an optimized antibody, naked or conjugated, may be warranted, particularly if eliminating FAP+ cells is documented to be both safe and required for efficacy.
"The second FAP-targeted therapy to be evaluated in the clinic was PT-100 (Talabostat), a dipeptide boronic acid (Val-boroPro). Again, it was well-tolerated, but ultimately failed in multiple Phase II clinical trials both as a monotherapy for metastatic colorectal cancer [113] and in combination with docetaxel for advanced non-small-cell lung cancer [114] or cisplatin for late-stage melanoma [115]. Emblematic of the problems associated with many of these early FAP-targeted approaches (i.e., lack of specificity) is that Val-boroPro was initially designed as a DPPIV inhibitor (IC50: <4 nM), later developed as FAP inhibitor (FAPI) (IC50: 560 nM), and recently undergone a rebirth as a DPP8/9 inhibitor (IC50: 4 and 100 nM, respectively) able to induce monocyte and macrophage pyroptosis [116– 119]. The latter property is the basis for its current clinical development by Bioxcel Therapeutics (rebranded as BXCL701) as a treatment for neuroendocrine prostate cancer in combination with anti-PD1 (pembrolizumab) (Phase Ib/II: NCT03910660) or as a monotherapy in a phase 0 ‘window of opportunity’ trial of pancreatic cancer (NCT04123574). The broad activity of PT-100/BXCL701 against members of the DPP family is not necessarily bad, though it may limit the therapeutic index given the lack of tumor-specific or -selective expression for many of these enzymes. Despite these concerns, the results of these new combination trials with immune checkpoint blockade will be eagerly anticipated.
"The repertoire of FAP-targeted strategies designed to kill FAP+ cells that have been explored preclinically is quite large, including antibody–drug conjugates, bispecific antibodies, vaccines, FAP-activated prodrugs and FAP- directed chimeric antigen receptors (CARs) [15,31]. The underlying rationale is that the restricted expression pattern and/or unique substrate specificity of FAP can be used to localize or selectively activate a cytotoxic molecule or immune response to the FAP+ TME. CARs are among the most advanced of these approaches thus far with several having been developed. Adoptive transfer of these anti-FAP CARs demonstrated efficacy against multiple preclinical tumor models including mesothelioma, melanoma, lung, colon, kidney and breast cancers [120–124]. One of these, again based on the F19 antibody, has already made it into early clinical testing with a first-in-man protocol for patients with malignant pleural mesothelioma (NCT01722149). This recently completed small study of four patients injected with re-directed FAP-specific T cells into the pleural effusion has only reported data from one patient reported thus far [125]. While no significant adverse events were reported, the trial was stopped prior to the estimated enrollment of six patients. There is preclinical evidence suggesting potential for significant toxicity with this approach as both a FAP-targeted CAR developed at the NIH by Rosenberg and colleagues in addition to conditional deletion of FAP+ cells using the diphtheria toxin-based approach described above produced cachexia and hematopoietic defects in recipient animals [122,126]. Other causes for potential concern regarding toxicity associated with FAP-targeted agents are related to FAP expression in pancreatic islet cells and fibroblastic reticular cells in lymph nodes [31,127]. It should be noted, however, that none of the other FAP-specific CARs or other FAP-targeted therapies described above produce similar toxicity, including when administered to some of the same models and genetic backgrounds. These discrepant results may be due to differences in the binding affinities and epitope specificities of antibodies used to generate the single chain variable fragments (scFv) that form the targeting moieties in these CAR constructs [123]. These differences may allow discrimination between FAP-high cells in the TME and FAP-low cells in normal tissues such as the BM and pancreas to spare toxicity in contrast to approaches that eliminate all or nearly all FAP+ cells in the body. Another possibility is that the total body irradiation preconditioning regimen used by Rosenberg et al. and not the other studies induced activation and proliferation of FAP+ MSCs in the BM, which support the hematopoietic stem cell (HSC) niche and aid in its recovery following irradiation [128]. Toxicity induced by eliminating rare HSC-supporting BM stromal cells was recently demonstrated using ROR1-targeted CARs following lymphodepletion with high dose irradiation or cyclophosphamide preconditioning regimens [129]. Additional considerations include species-specific differences in FAP biochemistry and cell biology between humans and mice. Most notably, the level of circulating FAP in mice is 20-fold that of humans [37]. The efficacy and safety profiles of other FAP-targeted CARs that are actively moving toward the clinic will be informative and guide future development of promising cell-based therapies directed against stromal targets.
"In the case of FAP-activated prodrugs, the unique post prolyl endopeptidase activity of FAP is used to selectively activate a cytotoxic molecule within the TME following systemic administration in an inactive prodrug form to spare toxicity to normal host tissues [130,131]. This logic has been used to engineer a variety of FAP-targeted prodrugs based on different cytotoxic ‘warheads’, including melittin, doxorubicin, bufadienolide, desacetylvinblastine mono- hydrazide, emetine and thapsigargin [132–139]. Because FAP is predominantly expressed by stromal cells with a low proliferative index in vivo in mice and humans, molecules with a proliferation-independent mechanism of action are particularly important for stromal-targeted therapies [134]. These different prodrugs have demonstrated significant antitumor efficacy against multiple tumor types, including breast, hepatocellular, lung and prostate cancers [132–139]. Overall, these different prodrug platforms were well-tolerated and showed reduced toxicity compared the parent compounds despite some activation in peripheral tissues [132–139]. The contribution of FAP-specific versus non targeted activation in these non tumor tissues is unclear. Many of these prodrugs are based on short peptide (2–7 amino acid) sequences that are potentially proteolyzed by related family members based on overlapping substrate specificities as discussed above. This is particularly of concern with POP as the N-termini for most of these substrates were ‘capped’ in such a way as to prevent recognition by strict exopeptidases, such as DDPIV. Again, the expression profile and enzymatic activity of FAP, POP and other S9 family members in plasma and tissues across different age groups and disease states has not been adequately characterized. These data along with more rigorous evaluation of these strategies using FAP-knockout hosts will likely be very informative for determining the FAP-specific efficacy at disease sites versus normal organ toxicities to safely move these approaches forward in the clinic. Additional work characterizing the immunologic impact of targeting FAP-positive cells via prodrugs or other strategies, timing of dosing regimens to maximize therapeutic benefit and combination treatments that exploit unique vulnerabilities with these FAP-depleted tumors are also needed. Current studies performed using pharmacologic-, immunotoxin- or cell-based approaches in syngeneic models support a re-polarization of the tumor-infiltrating immune profile toward an antitumor phenotype, including increasing the CD8:CD4 ratio and the expression of cytotoxic effector molecules in addition to suppressing macrophage and MDSC infiltration [96,123,140,141]. These antitumor immune responses can potentially be further augmented in the context of an antitumor vaccine [141] or using FAP-targeted 4-1BB agonist bispecific antibodies [142,143].
"FAP-directed radioconjugates for imaging & therapy
"As noted above, the first translated anti-FAP agent, sibrotuzumab, was radiolabeled with beta particle and single photon-emitting Iodine-131 (131I). This enabled planar gamma camera imaging and single photon emission computed tomography (CT) imaging to delineate biodistribution of 131I-sibrotuzumab in patients with advanced FAP-positive malignancies. The radioconjugate demonstrated high specific uptake in sites of tumor >1.5 cm, usually by 1–2 days post injection. However, the radio conjugate was eliminated slowly from normal organs and blood pool, resulting in high background signal and limited imaging quality [111], which discouraged further development.
"There is evidence suggesting that radiolabeled anti-FAP antibodies have antitumor potential in the preclinical setting. Two engineered anti-FAP antibodies, ESC11 and ESC14, labeled with the beta-emitting radionuclide Lutetium-177 (177Lu) have successfully extended survival of FAP-positive melanoma xenografts in nude mice [144]. BothantibodiesinducedrapidinternalizationofcellsurfaceFAP,providingtherapeuticimpactbyalteringtheTME. Emitted beta particles damaged targeted FAP-expressing cells and adjacent neighboring cells, which contributed to tumor suppression [144]. Beyond cancer, radiolabeled anti-FAP antibodies have been evaluated preclinically in other disease contexts as well, including inflammatory rheumatoid arthritis (RA), indicating the predictive value of FAP-targeted imaging [145–147]. Given the abundant FAP expression on fibroblast-like synoviocytes in RA, imaging studies using the anti-FAP antibody 28H1 labeled with Indium-111 (111In), Technetium-99 (99 mTc), or Zirconium-89 (89Zr) demonstrated selective accumulation in inflamed joints in mouse models. Radioactivity uptake was correlated with arthritis severity and can be quantified to monitor RA treatment efficacy [145–147].
"Small molecule conjugates derived from the potent FAP-inhibitor (4-quinolinoyl)-gly-2-cyanopyrrolidine scaf- fold [38] have recently been modified with a variety of radioisotopes for imaging and therapy. This class of compounds are termed FAPI, and many have been rapidly evaluated in preclinical and clinical contexts already. From the di- agnostic imaging perspective, Gallium-68 (68Ga)-FAPI positron emission tomography/CT (PET/CT) provides high-contrast images with quality comparable to that of the current clinical standard Fluorine-18 (18F)-FDG imag- ing. Proof-of-concept was provided by imaging metastatic breast and pancreatic cancer patients with 68Ga-FAPI-02, which demonstrated rapid accumulation in metastases [148]. 68Ga-FAPI-02 can be targeted to FAP-expressing cells with high affinity and then internalized rapidly. Its low uptake in normal tissues and fast clearance from circulation also contributed to high-contrast imaging [148]. To improve the uptake profile and increase tracer retention in tumors, a series of compounds based on FAPI-02 were developed – among them FAPI-04 has been most exten- sively investigated, which is based on a di-fluoronated proline analog of a highly specific small molecule FAPI [38]. Compared with 68Ga-FAPI-02, 68Ga-FAPI-04 showed higher accumulation and longer retention time in tumors without a significant increase in background activity [149]. Subsequently, 68Ga-FAPI-04 was evaluated in 80 patients with 28 different tumor types, including 13 prostate cancer patients, achieving remarkably high image contrast and excellent tumor delineation with PET/CT [150]. Further progress has been made with the recent development of FAPI-46, which has a longer tumor retention time than FAPI-04 [151]. Dosimetry and biodistribution studies of 68 Ga-FAPI-46 PET imaging in cancer patients has generated favorable profiles with clinical diagnostic potential [151]. FAPI PET imaging identified tumors not found with conventional CT and MRI in patients with glioblastomas and head and neck cancers, providing additional information for subsequent treatment planning [152,153]. Traditional 18F-FDG PET imaging, which identifies cells with high glucose consumption, is limited by poor performance in some cancers including liver, pancreatic, brain and prostate cancers. As an orthogonal approach and due to its low background uptake in brain and liver [154], 68Ga-FAPI PET imaging may enable high contrast imaging of tumor types not sensitive to 18F-FDG. A pilot study in patients with suspected hepatic carcinoma demonstrated the di- agnostic value of 68Ga-FAPI-04 PET imaging in this disease setting [155]. An additional advantage of this approach is that 68Ga-FAPI PET imaging is independent of blood sugar level, sparing patients from dietary preparation for 18F-FDG imaging. FAPI PET imaging can be performed 10 min to 1 h after injection, potentially reducing patient waiting time as well [154]. In addition to the quinoline-based FAPI derivatives, other FAPIs are emerging as promising imaging radiotracers, including UAMC1110-based compounds containing a squaramide linker, which have achieved comparable imaging quality relative to 68Ga-FAPI-04 in animal models [156].
"From the therapeutic perspective, FAPI work as enzymatic inhibitors in the TME. Additionally, FAPI derivatives can be chelated with beta- or alpha-emitting radioisotopes to irradiate tumor cells. Beta particle-emitting Yttrium-90 (90Y)-FAPI-04 was administered to one patient with metastatic breast cancer and associated with pain reduction [149]. In mouse models bearing FAP-positive human pancreatic xenografts, alpha particle-emitting Actinium-225 (225Ac)- FAPI-04 treatment targeted the tumor stroma leading to significant tumor growth suppression [157]. To amplify therapeutic benefit, future work is expected to focus on increasing tumor uptake and prolongation of tumor retention time. Preclinical studies have raised some concerns with respect to potential toxicity related to FAP- targeted approaches. Specifically, the short residency time in tumors may require higher injected quantities, which may consequently incur radiotoxic effects on clearance organs such as the kidney and bladder. This does not necessarily preclude the administration of radiotracer quantities for imaging purposes. It should be noted that all clinical studies reported thus far have reported a favorable safety profile; however, rigorous, phased trials are required for definitive conclusions.
"Conclusion & future perspective
"The previous decade has witnessed an explosion of molecular information that we possess about cancer cells. While an appreciation for the role of the TME in tumor progression is well-documented, characterization of these cells which are crucial to cancer’s progression and lethality, have lagged behind. Emerging tools and techniques are finally enabling the interrogation of these heterogeneous cellular and acellular components with ever-increasing resolution. As these technologies and our ability to integrate the resulting data matures, deeper mechanistic insights into precisely defined pathways driving the pro and anti tumorigenic effects of these heterogeneous populations will continue to emerge. For example, are these distinct populations derived from tissue-resident sources with tissue-specific functions, or are they recruited from systemic sources such as the BM and subsequently polarized in response to local factors produced in the tissue or TME? Is there a hierarchical relationship among different mesenchymal cell lineages with stem, progenitor and terminally differentiated pools akin to the hematopoietic system? Are these more differentiated phenotypes stable, or do they exist along a dynamic continuum that are polarized and potentially re-polarized to perform niche- and damage-specific functions? Is FAP the best target to overcome stromal barriers to immuno-oncological responses, or are there others that are either more suitable or complementary? Evidence in support of each of these overlapping and non exclusive viewpoints has emerged over the last few years [17,29,158–161], but we as a community are just beginning to scratch the surface of these complex relationships. A greater understanding of the underlying biology at the mesenchymal-immune interface in both normal tissue repair and pathophysiological processes such as cancer will reveal novel targets for intervention that can be either disrupted or restored for therapeutic benefit."
I got a FAPI PET/MRI this January. Was the first at that clinic, they had only done it for breast cancer so far. However, nothing was detected, apparently you need a higher PSA value for a FAPI PET than for a PSMA PET.
I had a PSA value of 2.7 and nothing was detected. The doctor said, you would need a higher PSA value than for a PSMA PET. So from my experience I would not get it done again below a PSA value of 8 to 10 ng/ml.
I think FAPI is of more value to different types of cancer. For PCa we have the PSMA PET which is more sensitive.
GP24 you seem to be plugged into all of the latest stuff. You had an interesting post from a few years ago ( healthunlocked.com/advanced... ). Before the LU-177 treatment what was your PSA? Afterwards? How long have you been dealing with PCa?
Usually you measure the success of a Lu177 therapy using PSMA PETs before and after the treatment. I did neoadjuvant and adjuvant Bicalutamide with the Lu177 therapy. That was my own therapy decision. Before I started with Bicalutamide I had a PSA value of 4.0 and after the Bicalutamide the PSA value stayed at 0.13 for a few months. It is now rising.
I wanted to get a Choline PET/CT at the clinic and I saw a new checkbox on the application form for FAPI. While I got my Choline PET/CT I asked who would be in charge of the FAPI PET. Then I called this doctor and he was interested to apply his new FAPI tracer to a PCa patient. This is how I got this FAPI PET.
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You had an interesting post from a few years ago ( 
came across Great John post….miss this guy so much
Melanoma and prostate cancer
Bone metastasis good news: OsteoDex got to phase 3 at last
An Update On My Father's PCa - Test Results/Treatment Plan
