Beyond PSMA - FAPI theranostics

(frequently updated)

Ideally, a new diagnostic and therapy ("theranostic") will have the following qualities:

• it will be theranostic for all cancer (high sensitivity)
• it will not be theranostic of anything that isn't cancer (high specificity)

In my previous article (see this link), we saw how PSMA heterogeneity can lead to treatment failure. PSMA is pretty specific, except for the salivary glands, the kidneys, and a few other places where expression is low. There is an opportunity to create ligands that are more sensitive and more specific.

Cancer is a tissue-based disease too

We often think of cancer as a cell-based disease: some rogue cells go wild, become immortal, and replicate out of control (see "The Hallmarks of Cancer"). In 1889, Stephen Paget put forth the "seed and soil" hypothesis: the cancer (the seed) thrives in "congenial soil." Not only does the seed find such soil, we have since learned that it actively creates its soil. This led to a new understanding of cancer as a tissue-based disease (see this link). What we call the "microenvironment" of the cancer is not just a passive player supporting the cancer cells; it actively sends signals to some cells (via extracellular vesicles - small "bubbles" containing microRNAs, enzymes, and essential proto-oncogenes) that cause them to become cancerous, and other cells to become supportive tissue - collagen, fat, blood vessels and nerves (collectively called stroma). They also suppress immune infiltration, attract regulatory T cells and certain kinds of macrophages that prevent immune response, and release cytokines that may cause or suppress inflammatory  response. The "reactive stroma" allows the tumor to grow and expand. This starts a positive feedback loop that enables the tumor (a collection of cancer cells and their stroma) to grow relentlessly.

Cancer-Associated Fibroblasts (CAF)

Fibroblasts are the most common cells in our connective tissue, which is the most prevalent tissue in our bodies. They create the collagen, fibronectin, the ground substance, adipose tissue, cytokines, growth factors, and other proteins that makes up the extracellular matrix that supports tissue architecture. When one cuts one's fingers, fibroblasts are activated and create the structure needed for the wound to heal. Fibroblasts are involved in cell adhesion, growth, migration and differentiation. Because they give rise to many different kinds of cell-precursers and proteins, they may be thought of as stem-cell-like (mesenchymal). The interested reader may wish to read this.

When cancer cells in the prostate go awry, they may, at some point go from being normal epithelial cells to being mesenchymal cells (called the epithelial-to-mesenchymal transition or EMT). EMT cells are capable of traveling outside of the prostate, where they can grow and clump into metastatic tumors, replete with cancer-associated fibroblasts (CAFs). The tumor can be thought of as a wound that doesn't finish healing and continually creates more wounds. In some cancers, 90% of the tumor volume is the stroma.

The tumor stroma can impair drug deliver, participate in drug resistance, and change the very nature of the cancer within (its phenotype). The stroma is where immunological agents and vascular-targeted agents have their effect (or lack of effect in the case of prostate cancer). See this link for a detailed discussion. It is also potentially targetable if it has a specific characteristic protein.

Fibroblast Activating Protein Inhibitor (FAPI)

There are several characteristic proteins in CAFs. One called Fibroblast Activating Protein (FAP) seems to be particularly useful. It is highly specific - it has only been found in cancers of epithelial origin (like prostate cancer), and never in healthy tissue. Immunohistochemical analysis of tumors has demonstrated a strong correlation between high FAP expression and worse prognosis. It has also been found in damaged tissue: inflamed tissues as in rheumatoid arthritis, myocardial infarction, liver cirrhosis, and atherosclerosis.

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.

Kratochwil et al. reported on the Ga-68-FAPI uptake in 28 different tumor types in 80 patients, in whom FDG, PSMA or other PET scans failed to detect much cancer. Good uptake was seen for almost all solid tumors. Above average uptake was seen for sarcoma, salivary, esophageal, cholangiocellular carcinoma, breast, lung, prostate, pancreatic, thymus, head and neck, ovarian, desmoid, chordoma, and colorectal cancer.

Lindner et al. reported on two metastatic breast cancer patients treated with Y-90-FAPI-04 as a proof of concept. They both reported an immediate reduction in pain. Dr. Baum at Bad Berka has treated 10 patients with a single low dose of Lu-177-FAP-2286. It accumulated in tumors, and had no associated toxicity. There was some symptomatic relief in some patients, and he plans to give them a second injection.

It is also possible to target fibroblast growth factors using inhibitors rather than radioactive agents, as described in this article.

Recently, we saw how two PET indicators were more sensitive than one. In that study, a GRPR-targeted ligand was paired in the same molecule with an integrin-targeted ligand. Integrins are created downstream from fibroblasts. GRPR is found in prostate cancer cells but is also highly expressed in gastrointestinal and CNS tissues. This limits its usefulness as a therapeutic target. However, the concept of double therapeutic targets is potentially useful for prostate cancer, where both PSMA and FAPI may be targeted.

Clinical Trials

In the US, preliminary clinical trials of FAPI-targeted PET indicators have begun.

• This one  at Stanford
• This one and this one at UCLA

So far, there are no therapeutic trials of Lu-177-FAPI that I am aware of, although the Haberkorn group may well be doing exploratory work. Big Pharma has taken notice; Lantheus, Novartis, Clovis, and Avacta have announced investments.

There is also a fibroblast inhibitor, erdafitinib, being explored in clinical trials:

• This one at M.D. Anderson
• This one at UW Seattle