Biology

Fibroblast Growth Factor Receptor 3 (FGFR3) is a cell surface receptor for ligands called fibroblast growth factors (FGFs). FGFs regulate the growth and differentiation of cells through complex combinatorial signaling pathways, including binding with a family of 4 tyrosine kinase FGF receptors (FGFRs). In humans, there are 22 FGFs and 4 FGF receptors (FGFR1, FGFR2, FGFR3, and FGFR4). Each of the FGFRs has an extracellular domain for ligand binding, a transmembrane domain, and an intracellular split tyrosine kinase domain. The extracellular ligand-binding regions have two or three immunoglobulin-line domains (IgD1 - 3).

The receptor FGFR3 in its native state is a monomer. The binding of FGF ligands to FGFR3 monomers leads to receptor dimerization, which then triggers a cascade of cellular events, starting with phosphorylation of the intracellular domain of the FGFR3 receptor followed by intracellular messengers, which ultimately regulate the growth and differentiation of cells.

B-701 is a human IgG1 monoclonal antibody that is specific for the FGFR3 and does not interact with the other FGFRs, i.e., FGFR1, FGFR2, or FGFR4. It is being used as an investigational treatment for medical conditions that are caused by activation of wild-type or mutated forms of FGFR3.

Metastatic Bladder Cancer

Bladder Cancer

In bladder cancer, inappropriate FGFR3 signaling is implicated in the pathogenesis of the majority of muscle invasive bladder cancer tumors, with 10-20% having activating FGFR3 mutations, fusions or amplification, and a significant percentage (≥50%) demonstrating over-expression of the receptor. Recently, others have validated FGFR3 as a driver for metastatic bladder cancer in human clinical studies. Activation of the receptor is believed to promote both the growth and survival of cancer cells. Thus, blocking its activity may not only directly inhibit tumor growth, but may also enhance the effectiveness of standard-of-care chemotherapy by depriving the tumor cells of potent survival signals. B-701 blocks the major mechanisms of FGFR3 activation that have been described in bladder cancer as shown below:

B-701 is Highly Unique in that it Blocks Multiple Mechanisms of FGFR3 activation associated with Bladder Cancer

Genetic Mutation
Causing auto-dimerization
Wild-type
Ligand-induced dimerization
Minority of invasive UCC* Majority of FGFR3 expressing UCC*

*UCC = urothelial cell carcinoma

B-701 as Monotherapy and in Combination

The ability of B-701 to suppress tumor growth in in-vivo bladder cancer models has been assessed either alone or in combination with chemotherapy. B-701 as a single agent potently inhibits the growth of bladder cancer tumors in xenografts expressing wild-type, mutant or fusion forms of FGFR3.

Further, in combination with standard of care chemotherapy for bladder cancer, B-701 greatly enhances the inhibition of the growth observed with single agent chemotherapy. Gemcitabine is part of a regimen used as first line treatment for metastatic bladder cancer while paclitaxel is commonly used as the standard of care for patients with refractory metastatic bladder cancer, thus we tested whether the combination of gemcitabine with B-701 or paclitaxel with B-701 would enhance the suppression of tumor growth as compared to either single agent. When mice bearing human tumor xenografts were treated with a combination of either B-701 and paclitaxel or B-701 and gemcitabine, tumor growth was highly suppressed and animal survival was dramatically extended. Effects observed by combining either paclitaxel or gemcitabine with B-701 were similar, suggesting that addition of B-701 to standard of care chemotherapy in either setting will be of clinical benefit.

Recently reported data that show FGFR3 expression and mutation are associated with poor immune cell infiltration into bladder cancers (Sweis et al 2015), suggesting that treatment with B-701 may enhance the efficacy of immune checkpoint inhibitors.

Patient Population

Bladder cancer is the sixth most commonly diagnosed cancer in the U.S.A. Over 90% of bladder cancer is urothelial cell carcinoma (UCC); other less frequent variants include squamous cell and adenocarcinoma. It is estimated that 74,000 new cases and 16,000 deaths from bladder cancer will occur in 2015 in the U.S. alone. There are an estimated 151,100 new cases and 52,400 deaths annually in Europe.

Seventy to 80% of bladder cancer is superficial, while 20-30% is invasive. In approximately 15% of the cases, the tumor extends beyond the wall of the bladder (stage T4). Prognosis of the metastatic T4 tumor type is poor despite surgery and systemic chemotherapy.

Therapeutic option for metastatic bladder cancer includes chemotherapy, generally gemcitabine in combination with cisplatin for 1st line treatment. Recently, atezolizumab has been approved for post-platinum metastatic bladder cancer. Despite the approval of atezolizumab, there remains a significant unmet medical need in this population, where average survival is still well below a year.

Achondroplasia

Achondroplasia is the most common form of disproportionate dwarfism and has been shown to be due to a single-point mutation in FGFR3.

Almost all FGFR3 mutations in achondroplasia are due to a mutation of glycine to arginine at position 380 of the transmembrane domain (G380R) of the FGFR3 protein. Achondroplasia is inherited in an autosomal dominant pattern; however, 80% of mutations are the result of a new spontaneous mutation.

Normally, FGFR3 signaling functions to negatively regulate normal bone growth, however, the mutation causes a gain-of-function of the FGFR3 protein, which increases the receptor signaling and enhances negative regulation of growth plate chondrocyte proliferation. This causes reduction in endochondral ossification, the process for producing longitudinal bone growth.

Manifestations may include proximal shortening of long bones of the limbs, macrocephaly, narrowing of the foramen magnum of the base of the skull, abnormal spinal curvature, facial hypoplasia, as well as other features.

Medical Complications of Achondroplasia

Achondroplasia is associated with a number of medical complications, due to the defect in endochondral bone formation. A partial list includes as follows:

  • Short stature, potential obesity
  • Middle ear infections and conductive hearing loss
  • Sleep apnea
  • Foramen magnum compression
  • Symptomatic hydrocephalus
  • Symptomatic lumbar spinal stenosis
  • Quality of life may be affected, particularly during school years
  • Sudden death, particularly in the 1st year of life

B-701 as a Potential Treatment for Achondroplasia

The single point activating mutation in the FGFR3 protein in achondroplasia may be an elegant and rational target for B-701, given its precise targeting of FGFR3.

Patient Population

Achondroplasia is an orphan condition and occurs in approximately 1 in 15,000 to 20,000 births with approximately 200 new cases per year in the US. In over 98% of individuals with achondroplasia, a single point-mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) is present.

Other Cancers

FGFR3 in Other Solid Tumors

In addition to bladder cancer, a number of other solid tumors have been reported to exhibit overexpression, mutation or fusion of FGFR3, including hepatocellular carcinoma, invasive breast carcinoma, squamous cell carcinoma of the lung, and oral squamous cell carcinoma.

In addition to playing a primary role in tumorigenesis, some preclinical studies have also demonstrated that FGFR3 can cause resistance to targeted therapies in melanoma, non-small cell lung cancer and breast cancer. For instance, FGFR3 signaling has been reported to be elevated and to induce resistance to vemurafenib, a B-RAF inhibitor, in an in vitro study of a vemurafenib-resistant melanoma cell line.

Multiple Myeloma

FGFR3 may play a role in multiple myeloma and could be a potential therapeutic target. Cytogenetic analysis identifies a risk factor for poor prognosis. One such abnormality, called the t(4;14) translocation, can be found in approximately 15-20% of patients with multiple myeloma and is associated with poor prognosis, including shorter survival. This translocation results in the up-regulation of two potential oncogenes, including FGFR3. Overexpression of FGFR3 on plasma cells occurs in the majority (approximately 75-92%) of patients with t(4;14)-positive multiple myeloma and in vitro confers chemo-resistance in myeloma cell cultures.

Publications

Advanced/Metastatic Bladder Cancer:

Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, Culine S, von der Maase H, Vaughn DJ, Rosenberg JE. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol 2010;28:1850-5.

Bernard-Pierrot I, Brams A, Dunois-Larde C, et al. Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis 2006;27:740-74.

Cancer Genome Atlas Research Network., Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507:315-22.

Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 1999;23:18-20.

Chaffer CL, Dopheide B, Savagner P, Thompson EW, Williams ED. Aberrant fibroblast growth factor receptor signaling in bladder and other cancers. Differentiation 2007;75:831-42.

Gómez-Román JJ, Saenz P, Cuevas González J, et al. Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res 2005;11:459-65.

Gust KM, McConkey DJ, Awrey S, et al. Fibroblast Growth Factor Receptor 3 is a Rational Therapeutic Target in Bladder Cancer. Mol Cancer Ther 2013;12:1245–54.

Qing J, Du X, Chen Y, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t (4; 14)-positive multiple myeloma in mice. J Clin Invest 2009;119:1077-9.

Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, Buchanan S, Henry JR, Starling JJ, Peng SB. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 2012;287:28087-98.

Sweis RF, Spranger S, Gajewski T. Molecular drivers of the non-T cell-inflamed tumor microenvironment in urothelial bladder cancer. J Clin Oncol 2015;33:suppl;abstr 4511.

Achondroplasia:

Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet 2007;370:162-72.

Ireland PJ, Pacey V, Zankl A, Edwards P, Johnston LM, Savarirayan R. Optimal management of complications associated with achondroplasia. Appl Clin Genet 2014;7:117-25

Laederich MB, Horton WA. FGFR3 targeting strategies for achondroplasia. Expert Rev Mol Med2012;14:e11.

Shirley ED, Ain MC Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg 2009;17:231-41.

Wright MJ, Irving MD. Clinical management of achondroplasia. Arch Dis Child 2012;97:129-34.

Multiple Myeloma:

Kalff A, Spencer A. The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies. Blood Cancer J 2012;2:e89.


© BioClin Therapeutics, Inc.