FGFR3 is frequently activated by mutation in urothelial carcinoma (UC) and represents a potential target for therapy. In multiple myeloma, both over-expression and mutation of FGFR3 contribute to tumour development. To define the population of UC patients who may benefit from FGFR-targeted therapy, we assessed both mutation and receptor over-expression in primary UCs from a population of new patients. Manual or laser capture microdissection was used to isolate pure tumour cell populations. Where present, non-invasive and invasive components in the same section were microdissected. A screen of the region of the highest tumour stage in each sample yielded a mutation frequency of 42%. Mutations comprised 61 single and five double mutations, all in hotspot codons previously identified in UC. There was a significant association of mutation with low tumour grade and stage. Subsequently, non-invasive areas from the 43 tumours with both non-invasive and invasive components were analysed separately; 18 of these had mutation in at least one region, including nine with mutation in all regions examined, eight with mutation in only the non-invasive component and one with different mutations in different regions. Of the eight with mutation in only the non-invasive component, six were predicted to represent a single tumour and two showed morphological dissimilarity of fragments within the block, indicating the possible presence of distinct tumour clones. Immunohistochemistry showed over-expression of FGFR3 protein in many tumours compared to normal bladder and ureteric controls. Increased expression was associated with mutation (85% of mutant tumours showed high-level expression). Overall, 42% of tumours with no detectable mutation showed over-expression, including many muscle-invasive tumours. This may represent a non-mutant subset of tumours in which FGFR3 signalling contributes to the transformed phenotype and which may benefit from FGFR-targeted therapies.

/pdf/fgfr3-protein-expression-and-its-relationship-to-mutation-457eol6zgy.pdf

FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer

Although non-invasive bladder tumours (pTa) are the most common group of bladder tumours at presentation, there has until recently been relatively little information on their molecular biology. Thus it was of great interest when mutations in the FGF receptor 3 (FGFR3) were identified in bladder tumours and it became apparent that these were most common in tumours of low grade and stage. Since the initial description of activating mutations of FGFR3, there have been numerous studies confirming the frequency and spectrum of these mutations in bladder cancers of all grades and stages. Mutation screening techniques have evolved and improved. FGFR3 mutation has been assessed as a predictive biomarker in tumour tissues and as a diagnostic biomarker in urine. Efforts have been made to understand the function of FGFR3 in urothelial and other cells. Although our understanding of FGFR3 function is incomplete, it is already apparent that this may represent an important therapeutic target not only in non-invasive bladder cancer but also in a significant number of invasive tumours. This review summarises the current state of knowledge of this interesting receptor in urothelial carcinoma (UC).

/pdf/role-of-fgfr3-in-urothelial-cell-carcinoma-biomarker-and-3g8nbdzpts.pdf

Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target.

Allogeneic hematopoietic SCT is well established as a potentially curative therapy for children and adults with both malignant and nonmalignant diseases. However, myeloablative SCT is associated with significant short- and long-term complications. The goals of a reduced intensity-conditioning (RIC) regimen are to prevent graft rejection and establish stable donor-derived hematopoiesis at a level sufficient for cure of the underlying disease and, in patients with hematologic malignancy, to provide a GVL effect, while decreasing the short- and long-term complications associated with myeloablative conditioning therapy. RIC regimens have enabled SCT to be performed in children with preexisting comorbidities that preclude conventional conditioning. RIC-SCT has been most extensively studied in patients with nonmalignant disorders and for some of these, including primary immunodeficiencies and hemophagocytic lymphohistiocytosis, sufficient data now exist to support its routine use even in patients without comorbidity. Less data exist on RIC-SCT for children with hematologic malignancies and at present this should be restricted to children who are not candidates for, or have relapsed after, myeloablative SCT. Here we review available data on the use of RIC-SCT in pediatric patients, highlighting important clinical lessons and areas that require further study.

Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases.

Bladder cancer presents several challenges in clinical management. For the large group of noninvasive tumors, key problems are the development of multiple recurrences that require long-term surveillance and a lack of effective therapies to prevent recurrence. For the smaller group of poor prognosis patients with invasive disease, novel therapies are urgently needed. The identification of mutations of FGF receptor 3 (FGFR3) in most noninvasive bladder tumors and the recent finding of overexpression of this receptor not only in superficial tumors but also in many invasive bladder cancers has generated optimism that therapies targeting this receptor tyrosine kinase may have major application in the treatment of urothelial cancers. There is little information on the other members of this receptor family apart from FGFR2, which is implicated as a tumor suppressor. Recent preclinical evaluations of FGFR3 as a therapeutic target have provided a strong impetus for the development of targeted agents for clinical use.

Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors

Transplantation-related mortality, graft failure, and survival after reduced-toxicity conditioning and allogeneic hematopoietic stem cell transplantation in 100 consecutive pediatric recipients.

Purpose: Myeloablative allogeneic stem cell transplantation (SCT) has been successful in the treatment of childhood acute myeloid leukemia (AML), but may be associated with significant toxicity and recurrent disease. Reduced-intensity allogeneic SCT may offer a less toxic approach to patients with AML. Targeted immunotherapy with gemtuzumab ozogamicin has been shown to be safe, well tolerated in children, and, as a single agent, gemtuzumab ozogamicin has induced responses in 30% of patients with recurrent CD33 + AML. There are no safety data with gemtuzumab ozogamicin post allogeneic SCT in children. Therefore, we explored the feasibility and toxicity of targeted immunotherapy following reduced-intensity allogeneic SCT in children with CD33 + AML. Experimental Design: Eight patients with CD33 + AML received a reduced-intensity allogeneic SCT following fludarabine 30 mg/m 2 for 6 days and busulfan 3.2 mg/kg ( Results: Day 30 and day 60 donor chimerisms in seven of eight evaluable patients were 96 ± 2% ( n = 7) and 94 ± 3% ( n = 6), respectively. Five of six patients (too early for one patient) received two doses of gemtuzumab ozogamicin and one patient received only one dose. After each dose, all patients developed grade 4 neutropenia, with recovery on median days 16 and 13, respectively, after dose 1 and dose 2. Grade 4 thrombocytopenia was only observed in 2 of 11 gemtuzumab ozogamicin courses. No patients have developed dose-limiting toxicity secondary to gemtuzumab ozogamicin. Conclusions: The administration of gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with average risk AML is feasible and well tolerated with minimal toxicity. The maximal tolerated dose has yet to be determined for gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with CD33 + AML. Additional studies in a larger group of patients will be required to adequately assess the safety of this approach.

https://clincancerres.aacrjournals.org/content/clincanres/11/19/7164s.full.pdf

Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia.

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Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia.