Therapeutic Opportunities in the Intrinsic Subtypes of Muscle-Invasive Bladder Cancer

McConkey, David J.; Choi, Woonyoung; Ochoa, Andrea; Siefker-Radtke, Arlene; Czerniak, Bogdan; Dinney, Colin P.

doi:10.1016/j.hoc.2014.11.003

Cited by 60 publications

(56 citation statements)

References 69 publications

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“…Similarly, the intrinsic MIBC subtypes contain features that may also influence their responses to conventional and targeted cancer therapies [39]. As is true in invasive breast cancer, neoadjuvant chemotherapy is considered standard-of-care for high-risk MIBC, and down-staging to no residual MIBC at cystectomy is predictive of excellent long-term clinical outcomes [40].…”

Section: Implications For Therapymentioning

confidence: 99%

“…Basal MIBCs are also enriched with gene expression signatures predictive of active STAT3 [39], and preclinical studies have directly implicated STAT3 in basal bladder cancer tumorigenesis [32]. Direct inhibitors of STAT3 are still in preclinical development, and these agents would be predicted to be most active in basal cancers.…”

Section: Candidate Biological Targets In Basal Cancersmentioning

confidence: 99%

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Genetic subtypes of invasive bladder cancer

McConkey

Choi

Dinney

2015

Current Opinion in Urology

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Like their breast cancer counterparts, basal bladder cancers are characterized by poor clinical outcomes in the absence of effective systemic therapy, but a large fraction of them do respond to neoadjuvant chemotherapy, suggesting that the tumors should be managed aggressively. On the contrary, tumors that belong to the 'p53-like' subtype tend to be chemoresistant, so patients with these tumors should probably be managed differently. It seems likely that prospective identification of tumor intrinsic subtype membership could complement the use of DNA-based biomarkers to identify the groups of patients who will benefit the most from chemotherapy and targeted agents.

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Section: Implications For Therapymentioning

confidence: 99%

Section: Candidate Biological Targets In Basal Cancersmentioning

confidence: 99%

Genetic subtypes of invasive bladder cancer

McConkey

Choi

Dinney

2015

Current Opinion in Urology

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“…However, both datasets suggested low levels of activity in luminal 1 tumors. Luminal 1 tumors appear more immunoquiescent, lacking the immune markers expressed in luminal 2 and at even higher levels in basal tumors [19]. The enrichment for FGFR3 mutations in the luminal 1 subtype [19], suggests the potential for FGFR3 inhibitors as a therapeutic in these immunologically cold tumors.…”

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confidence: 99%

“…Luminal 1 tumors appear more immunoquiescent, lacking the immune markers expressed in luminal 2 and at even higher levels in basal tumors [19]. The enrichment for FGFR3 mutations in the luminal 1 subtype [19], suggests the potential for FGFR3 inhibitors as a therapeutic in these immunologically cold tumors. Clinical activity also appeared lower in the basal 2 tumors, a group with the highest levels of expression of immune markers.…”

mentioning

confidence: 99%

“…Clinical activity also appeared lower in the basal 2 tumors, a group with the highest levels of expression of immune markers. These basal 2 tumors also have a claudin-low signature associated with epithelial-mesenchymal transition (EMT) [19]. The presence of myeloid-derived suppressor cells associated with these EMT tumors suggest a potential pairing of checkpoint inhibitors with therapies that deplete or control immune regulatory cells [20].…”

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confidence: 99%

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Five New Therapies or Just One New Treatment? A Critical Look at Immune Checkpoint Inhibition in Urothelial Cancer

2017

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" It is clear that we are just at the beginning of the new immune era in the treatment of cancer.The field is ripe for progress in studying further combinations that enhance the activity of the immune system and overcome pathways of resistance " Physicians have been enlivened by the first major breakthrough in over 30 years in metastatic urothelial cancer (UC) with the approval of five new therapeutics involved in immune checkpoint blockade. These newly approved agents in UC are monoclonal antibodies blocking PD-L1 including atezolizumab, durvalumab and avelumab, or monoclonal antibodies against PD-1 including nivolumab and pembrolizumab. PD-1, a checkpoint protein present on activated T cells, interferes with T-cell antigen receptor mediated signaling to act as an 'off-switch' and thus avoid immune attack on self-cells [1]. PD-L1 protein is present on normal cells and binds PD-1, which allows this downregulation of T-cell response. However, many cancer cells also express PD-L1, allowing them to masquerade as normal cells and avoid immune-mediated attack. By interfering with the PD-1/PD-L1 interaction, these drugs allow for a heightened immune attack on cancer cells.The concept of immune-mediated therapy is not new in UC. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, has been used for four decades in superficial bladder cancer and is thought to allow a more robust local inflammatory response via intravesicular treatment [2,3]. IFN-α has also been used as an immune modulatory approach, given both intravesically in combination with BCG [4,5], and systemically in combination with chemotherapy, with variable activity reported [6]. A more recent gene therapy approach using an IFN-α-expressing adenovirus has resulted in more sustained levels of IFN-α in the bladder [7]. Ipilimumab, an anti-CTLA antibody, has been explored in localized bladder cancer and resulted in tumor immune infiltrates and pathological clinical responses in 3 of 12 patients treated with neoadjuvant ipilimumab [8].Atezolizumab was first granted accelerated US FDA approval in May 2016 following front line platinum-based therapy with an observed response rate of 15%, which was an improvement over the 10% historic control [9]. Activity was observed in both PD-L1 positive and negative tumors, resulting in approval regardless of PD-L1 status [9]. Of the 45 responders, 38 patients had ongoing durable responses at 11.7 months. Subsequently, nivolumab, durvalumab, avelumab and pembrolizumab were approved with similar response rates around 15-21% and trend toward durable responses in each trial [10][11][12]. Pembrolizumab is currently the only immune checkpoint inhibitor with Level I evidence from a Phase III trial showing improved survival compared with single agent taxanes. A recent update on a Phase III study suggests atezolizumab as a second-line therapy has not achieved its survival end point [13]. Further data from this trial are needed to determine whether this was due to trial design, due to crossover of the taxane...

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Medical Treatment with Targeted Therapy for Metastatic Urothelial Bladder Carcinoma

Alhalabi

Gao

2021

Urinary Bladder Pathology

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Therapeutic Opportunities in the Intrinsic Subtypes of Muscle-Invasive Bladder Cancer

Cited by 60 publications

References 69 publications

Genetic subtypes of invasive bladder cancer

Genetic subtypes of invasive bladder cancer

Five New Therapies or Just One New Treatment? A Critical Look at Immune Checkpoint Inhibition in Urothelial Cancer

Medical Treatment with Targeted Therapy for Metastatic Urothelial Bladder Carcinoma

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