Therapeutic Landscape Beyond Immunotherapy in Advanced Urothelial Carcinoma: Moving Past the Checkpoint

Tripathi, Abhishek; MacDougall, Kira; Sonpavde, Guru

doi:10.1007/s40265-022-01802-3

Cited by 7 publications

(12 citation statements)

References 81 publications

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“…247,248 In addition, the tyrosine kinase inhibitor (TKI) has been shown to have a tangible effect, and its use has been approved in urothelial patients with FGFR abnormalities. 249,250 Bladder cancer is the most frequently occurring tumor with FGFR3 mutations, with an incidence of 9−11%. [251][252][253] In bladder cancer, activation of the SRC pathway by FGFR3 leads to resistance of tumor cells to FGFR inhibitors, such as infigratinib or erdafitinib.…”

Section: Fgfr3 Functions As a Promoter In Tumorsmentioning

confidence: 99%

“…Abnormal activation of FGFR3 has been recognized to play a cancer‐promoting role in patients with urothelial cancer, especially bladder cancer, in which FGFR3 mutations, rearrangements, and fusions are the most common 247,248 . In addition, the tyrosine kinase inhibitor (TKI) has been shown to have a tangible effect, and its use has been approved in urothelial patients with FGFR abnormalities 249,250 …”

Section: Fgfr Is Involved In Human Tumorsmentioning

confidence: 99%

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FGFR families: biological functions and therapeutic interventions in tumors

Liu,

Huang,

Yan

et al. 2023

MedComm

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There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1–FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase, phosphoinositide 3‐kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well‐known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.

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Section: Fgfr3 Functions As a Promoter In Tumorsmentioning

confidence: 99%

Section: Fgfr Is Involved In Human Tumorsmentioning

confidence: 99%

FGFR families: biological functions and therapeutic interventions in tumors

Liu,

Huang,

Yan

et al. 2023

MedComm

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“…The results from phase II-III clinical studies have shown that these new therapies have efficacy rates (3 and 12 months) of 40-82% and 17-44%, respectively, and the long-term efficacy remains to be further observed [24][25][26][27] Recently, targeted agents such as the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib and ADCs have demonstrated robust efficacy after progression on prior chemotherapy and immunotherapy in advanced BCa. [28] Compared to erdafitinib, ADCs are available to more BCa patients due to the high expression rate of target proteins. A head-to-head comparison of expression differences in HER2, NECTIN4, and TROP2 demonstrated that the majority of BCa expressed at least one ADC target.…”

Section: Discussionmentioning

confidence: 99%

A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer

Hong,

Chen,

Wang

et al. 2023

Advanced Science

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More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, intravesical instillation for NMIBC treatment. In this preclinical study, it is revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48‐ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48‐ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase‐dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48‐ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate‐buffered saline control. The potential toxicity of intravesical RC48‐ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48‐ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48‐ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48‐ADC in NMIBC patients.

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“…Overall survival in patients after cystectomy correlates with pathologic stage, and about 30% of patients can experience recurrence at a median of 12 months after cystectomy 13456789101112131415. Unfortunately, the five year overall survival of patients with distant metastasis remains low 13.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the five year overall survival of patients with distant metastasis remains low 13. Relevant clinicopathologic factors include the number and size of tumors, presurgical recurrence rates, T stage, presence of carcinoma in situ, and histologic grade and nodal status 35101214161718192021222324…”

Section: Introductionmentioning

confidence: 99%

Advances in diagnosis and treatment of bladder cancer

Lopez-Beltran,

Cookson,

Guercio

et al. 2024

BMJ

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Bladder cancer remains a leading cause of cancer death worldwide and is associated with substantial impacts on patient quality of life, morbidity, mortality, and cost to the healthcare system. Gross hematuria frequently precedes the diagnosis of bladder cancer. Non-muscle-invasive bladder cancer (NMIBC) is managed initially with transurethral resection of a bladder tumor (TURBT), followed by a risk stratified approach to adjuvant intravesical therapy (IVe), and is associated with an overall survival of 90%. However, cure rates remain lower for muscle invasive bladder cancer (MIBC) owing to a variety of factors. NMIBC and MIBC groupings are heterogeneous and have unique pathological and molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers and luminal and basal molecular subtypes of MIBC with distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) is the gold standard treatment for high grade and high risk NMIBC to reduce or prevent both recurrence and progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. IVe gene therapy and combination IVe chemotherapy have recently been completed, with promising results. For localized MIBC, essential goals are improving care and reducing morbidity following cystectomy or bladder preserving strategies. In metastatic disease, advances in understanding of the genomic landscape and tumor microenvironment have led to the implementation of immune checkpoint inhibitors, targeted treatments, and antibody-drug conjugates. Defining better selection criteria to identify the patients most likely to benefit from a specific treatment is an urgent need.

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Therapeutic Landscape Beyond Immunotherapy in Advanced Urothelial Carcinoma: Moving Past the Checkpoint

Cited by 7 publications

References 81 publications

FGFR families: biological functions and therapeutic interventions in tumors

FGFR families: biological functions and therapeutic interventions in tumors

A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer

Advances in diagnosis and treatment of bladder cancer

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