Emerging therapeutic agents for genitourinary cancers

Zarrabi, Kevin; Paroya, A.; Wu, Shenhong

doi:10.1186/s13045-019-0780-z

Cited by 38 publications

(24 citation statements)

References 190 publications

(208 reference statements)

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“…As such, targeted therapies in RCC have become essential in the management of the disease when it has spread beyond the clinically localized setting. Numerous pathways including VEGF 1-3 , mTOR, PDGFRα, MET, FGFR 1-4 , RET, KIT, and AXL have been targeted by established and emerging therapies [12]. Various agents have been tested in the pre-clinical setting using PDX models to investigate tumor response.…”

Section: Correlation With Therapy Response and Chemosensitivitymentioning

confidence: 99%

“…Immuno-oncology is an exciting and rapidly evolving field, particularly with the treatment of advanced bladder and kidney cancers. This therapeutic revolution has seen the recent approval of numerous immune checkpoint inhibitors [12]. Unfortunately, the utilization of immune-deficient mice limits the ability to test therapies that rely on T cell anti-tumor activity, significantly restricting the applicability of PDX models in the testing of immune checkpoint inhibitors.…”

Section: Immunotherapy Testingmentioning

confidence: 99%

“…Though there have been encouraging results from clinical trials involving newly developed immune-checkpoint inhibitors, cisplatin-based chemotherapy remains the mainstay of treatment in both the neoadjuvant and metastatic setting. Chemotherapy portends a relatively modest 5-7% overall survival benefit in the neoadjuvant setting, and the overall response rate is well below 50% in metastatic [12,13]. These data taken together underscore the need to develop better treatments, and more importantly the need to predict individual patient therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

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Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma

Tracey

Murray

Coleman

et al. 2020

Cancers

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The engraftment of human tumor tissues into immunodeficient host mice to generate patient-derived xenograft (PDX) models has become increasingly utilized for many types of cancers. By capturing the unique genomic and molecular properties of the parental tumor, PDX models enable analysis of patient-specific clinical responses. PDX models are an important platform to address the contribution of inter-tumoral heterogeneity to therapeutic sensitivity, tumor evolution, and the mechanisms of treatment resistance. With the increasingly important role played by targeted therapies in urological malignancies, the establishment of representative PDX models can contribute to improved facilitation and adoption of precision medicine. In this review of the evolving role of the PDX in urothelial cancer and kidney cancer, we discuss the essential elements of successful graft development, effective translational application, and future directions for clinical models.

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Section: Correlation With Therapy Response and Chemosensitivitymentioning

confidence: 99%

Section: Immunotherapy Testingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma

Tracey

Murray

Coleman

et al. 2020

Cancers

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“…Avelumab is currently applied for treatment of metastatic Merkel Cell Carcinoma, 55 Renal Cell Cancer 56 and Urothelial Carcinoma. 57 With respect to NSCLC, in a large open-label, phase III clinical trial enrolling 792 patients, avelumab treatment did not improve overall survival in patients with platinum-treated PD-L1-positive tumors when compared to docetaxel. 58 Thus, avelumab failed approval status as a therapy for NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC): a systematic literature review

et al. 2020

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Background: Therapeutic strategies with immune checkpoint inhibitors (ICIs) counteract the immunosuppressive effects of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1). ICI treatment has emerged in first-and second-line therapy of non-small cell lung cancer (NSCLC). As immunotherapeutic treatment with ICIs is a dynamic field where new drugs and combinations are constantly evaluated, we conducted an up-to-date systematic review on comparative efficacy and safety in patients with advanced NSCLC. Methods: We searched PubMed up to February 2020 and Embase, CENTRAL, and clinical trial registries up to August 2018. Additionally, we checked reference lists. We dually screened titles, abstracts and, subsequently, full-texts for eligibility. Two reviewers assessed the risk of bias and graded the certainty of evidence following GRADE (Grading of Recommendations Assessment, Development and Evaluation). For second-line therapy, we performed random-effects meta-analyses. Due to considerable clinical heterogeneity, we reported first-line results narratively. Results: Of 1497 references, we identified 22 relevant publications of 16 studies. For first-line therapy, a combination of an ICI with chemotherapy improved progression-free survival and overall survival compared to chemotherapy but increased the risk of serious adverse events. Single-agent pembrolizumab increased overall and progression-free survival in patients with PD-L1 expression of ≥50% and resulted in less TRAE than chemotherapy. Compared to placebo, maintenance therapy with durvalumab increased overall and progression-free survival at the downside of higher risk of TRAE. For second-line therapy, a random-effects metaanalysis yielded a statistically significantly improved overall survival (OS) and progression-free survival (PFS) for ICIs compared to docetaxel (HR 0.69; 95% CI: 0.63-0.75 for OS; HR 0.85; 95% CI: 0.77 − 0.93 for PFS; 6 studies, 3478 patients; median OS benefit in months: 2.4 to 4.2). In meta-analysis, risk of any treatment-related adverse events of any grade was lower for ICI than docetaxel as second-line therapy (RR 0.76, 95% CI: 0.73-0.79; 6 studies, 3763 patients). Conclusion: In first-line therapy of patients with advanced NSCLC, ICI is effective when combined with chemotherapy not depending on PD-L1 expression, or as monotherapy in high PD-L1 expressing tumors. For second-line therapy, single-agent ICI improves efficacy and safety compared to docetaxel.

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“…Recently, FLT3 inhibitors and inhibitors of isocitrate dehydrogenases (IDH1 and IDH2) significantly enhanced the armamentarium for AML therapy [31][32][33][34][35]. TKIs targeting a variety of oncoproteins, such as EGFR, ALK, HER2, FGFR, VEGFR, RET, MET, to name a few, have brought revolutions in the therapy of non-small cell lung cancer, breast cancer, bladder cancer, liver cancer, and renal cell carcinoma [5,6,[36][37][38][39][40][41][42]. BRAF inhibitors targeting serine /threonine kinases lead to major advances in the therapy of malignant melanoma [43,44].…”

Section: Small Molecule Inhibitors (Smi) As Targeted Agents: Small Pimentioning

confidence: 99%

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

Liu

2019

J Hematol Oncol

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New advances in the design and manufacture of monoclonal antibodies, bispecific T cell engagers, and antibodydrug conjugates make the antibody-directed agents more powerful with less toxicities. Small molecule inhibitors are routinely used now as oral targeted agents for multiple cancers. The discoveries of PD1 and PD-L1 as negative immune checkpoints for T cells have led to the revolution of modern cancer immunotherapy. Multiple agents targeting PD1, PD-L1, or CTLA-4 are widely applied as immune checkpoint inhibitors (ICIs) which alleviate the suppression of immune regulatory machineries and lead to immunoablation of once highly refractory cancers such as stage IV lung cancer. Tisagenlecleucel and axicabtagene ciloleucel are the two approved CD19-targeted chimeric antigen receptor (CAR) T cell products. Several CART cell platforms targeting B cell maturation antigen (BCMA) are under active clinical trials for refractory and/or relapsed multiple myeloma. Still more targets such as CLL-1, EGFR, NKG2D and mesothelin are being directed in CART cell trials for leukemia and solid tumors. Increasing numbers of novel agents are being studied to target cancer-intrinsic oncogenic pathways as well as immune checkpoints. One such an example is targeting CD47 on macrophages which represents a "do-not-eat-me" immune checkpoint. Fueling the current excitement of cancer medicine includes also TCR-T cells, TCR-like antibodies, cancer vaccines and oncolytic viruses.

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Emerging therapeutic agents for genitourinary cancers

Cited by 38 publications

References 190 publications

Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma

Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma

Efficacy and safety of immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC): a systematic literature review

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

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