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Medical Oncology
Published in: Medical Oncology 12/2023

13-11-2023 | Kidney Cancer | Review Article

Molecular insight into renal cancer and latest therapeutic approaches to tackle it: an updated review

Authors: Reshma Murali, Abilash Valsala Gopalakrishnan

Published in: Medical Oncology | Issue 12/2023

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Abstract

Renal cell carcinoma (RCC) is one of the most lethal genitourinary cancers, with the highest mortality rate, and may remain undetected throughout its development. RCC can be sporadic or hereditary. Exploring the underlying genetic abnormalities in RCC will have important implications for understanding the origins of nonhereditary renal cancers. The treatment of RCC has evolved over centuries from the era of cytokines to targeted therapy to immunotherapy. A surgical cure is the primary treatment modality, especially for organ-confined diseases. Furthermore, the urologic oncology community focuses on nephron-sparing surgical approaches and ablative procedures when small renal masses are detected incidentally in conjunction with interventional radiologists. In addition to new combination therapies approved for RCC treatment, several trials have been conducted to investigate the potential benefits of certain drugs. This may lead to durable responses and more extended survival benefits for patients with metastatic RCC (mRCC). Several approved drugs have reduced the mortality rate of patients with RCC by targeting VEGF signaling and mTOR. This review better explains the signaling pathways involved in the RCC progression, oncometabolites, and essential biomarkers in RCC that can be used for its diagnosis. Further, it provides an overview of the characteristics of RCC carcinogenesis to assist in combating treatment resistance, as well as details about the current management and future therapeutic options. In the future, multimodal and integrated care will be available, with new treatment options emerging as we learn more about the disease.
Literature
1.
Kathuria-Prakash N, Drolen C, Hannigan CA, Drakaki A. Immunotherapy and metastatic renal cell carcinoma: a review of new treatment approaches. Life Basel. 2021;12(1):24.PubMedPubMedCentral
2.
Lotan Y, et al. Renal-cell carcinoma risk estimates based on participants in the prostate, lung, colorectal, and ovarian cancer screening trial and national lung screening trial. Urol Oncol. 2016;34(4):167.e9-16.PubMed
3.
Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. Int J Cancer. 2005;114(1):101–8.PubMed
4.
Ljungberg B, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24.PubMed
5.
Meyer AR, Allaf ME, Gorin MA. Epidemiology and risk factors of renal cell carcinoma. In: Gorin M, Allaf M, editors. Diagnosis and surgical management of renal tumors. Cham: Springer; 2019.
6.
Oto J, et al. Urinary microRNAs: looking for a new tool in diagnosis, prognosis, and monitoring of renal cancer. Curr Urol Rep. 2020;21(2):11.PubMed
7.
Bhatt JR, Finelli A. Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat Rev Urol. 2014;11(9):517–25.PubMed
8.
Jones JM, et al. Setting research priorities for kidney cancer. Eur Urol. 2017;72(6):861–4.PubMed
9.
Rossi SH, Klatte T, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol. 2018;36(9):1341–53.PubMedPubMedCentral
10.
Delahunt B, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37(10):1490–504.PubMed
11.
Comprehensive molecular characterization of papillary renal-cell carcinoma. NEJM 374(2):135–145, 2015.
12.
Yamazaki K, Sakamoto M, Ohta T, Kanai Y, Ohki M, Hirohashi S. Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene. 2003;22(6):847–52.PubMed
13.
Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008;8(11):865–73.PubMed
14.
U. Food and D. Administration, "FDA approves avelumab plus axitinib for renal cell carcinoma," ed, 2021.
15.
Ellimoottil C, et al. New modalities for evaluation and surveillance of complex renal cysts. J Urol. 2014;192(6):1604–11.PubMed
16.
Gray RE, Harris GT. Renal cell carcinoma: diagnosis and management. Am Fam Phys. 2019;99(3):179–84.
17.
Shah S, Watnick T, Atta MG. Not all renal cysts are created equal. Lancet. 2010;376(9745):1024.PubMed
18.
Capitanio U, Montorsi F. Renal cancer. Lancet. 2016;387(10021):894–906.PubMed
19.
Braun DA, et al. Beyond conventional immune-checkpoint inhibition—novel immunotherapies for renal cell carcinoma. Nat Rev Clin Oncol. 2021;18(4):199–214.PubMedPubMedCentral
20.
Singh D. Current updates and future perspectives on the management of renal cell carcinoma. Life Sci. 2021;264:118632.PubMed
21.
Bui TO, Dao VT, Nguyen VT, Feugeas JP, Pamoukdjian F, Bousquet G. Genomics of clear-cell renal cell carcinoma: a systematic review and meta-analysis. Eur Urol. 2022;81(4):349–61.PubMed
22.
Bosma NA, et al. Efficacy and safety of first-line systemic therapy for metastatic renal cell carcinoma: a systematic review and network meta-analysis. Eur Urol Open Sci. 2022;37:14–26.PubMedPubMedCentral
23.
Karner C, Kew K, Wakefield V, Masento N, Edwards SJ. Targeted therapies for previously treated advanced or metastatic renal cell carcinoma: systematic review and network meta-analysis. BMJ Open. 2019;9(3):e024691.PubMedPubMedCentral
24.
Pandey J, Syed W. Renal Cancer. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022.
25.
Ravaud A, et al. Adjuvant Sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23) 2246–54.PubMed
26.
Naomi B, et al. Adjuvant sunitinib or sorafenib for high-risk non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind placebo-controlled randomised phase 3 trial. The Lancet. 2016;387(10032):2008–16.
27.
Motzer J, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017;35(35) 3916–23.PubMedPubMedCentral
28.
Gross-Goupil M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III randomized ATLAS trial. Ann Oncol. 2018;29(12) 2371–8.PubMedPubMedCentral
29.
(2021, 2023). SEER cancer stat facts: kidney and renal pelvis cancer.
30.
31.
Makino T, et al. Epidemiology and prevention of renal cell carcinoma. Cancers (Basel). 2022;14(16):4059.PubMed
32.
Scholtes MP, Alberts AR, Iflé IG, Verhagen PC, van der Veldt AA, Zuiverloon TC. Biomarker-oriented therapy in bladder and renal cancer. Int J Mol Sci. 2021;22(6):2832.PubMedPubMedCentral
33.
Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, Bray F. International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol. 2015;67(3):519–30.PubMed
34.
Levi F, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 2008;101(8):949–58.PubMed
35.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.PubMed
36.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.PubMed
37.
Thompson RH, et al. Renal cell carcinoma in young and old patients–is there a difference? J Urol. 2008;180(4):1262–6 (discussion 1266).PubMedPubMedCentral
38.
Yong C, Stewart GD, Frezza C. Oncometabolites in renal cancer. Nat Rev Nephrol. 2020;16(3):156–72.PubMed
39.
Network CGAR. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9.
40.
Du W, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8(1):1769.PubMedPubMedCentral
41.
Mullen AR, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011;481(7381):385–8.PubMedPubMedCentral
42.
Wang H, et al. Oncometabolite L-2-hydroxyglurate directly induces vasculogenic mimicry through PHLDB2 in renal cell carcinoma. Int J Cancer. 2021;148(7):1743–55.PubMedPubMedCentral
43.
Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling. J Biol Chem. 2014;289(35):24691–9.PubMedPubMedCentral
44.
McEvoy CR, et al. SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response. NPJ Precis Oncol. 2018;2:9.PubMedPubMedCentral
45.
Shim EH, et al. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 2014;4(11):1290–8.PubMedPubMedCentral
46.
Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;7(5):277–85.PubMedPubMedCentral
47.
Haake SM, Weyandt JD, Rathmell WK. Insights into the genetic basis of the renal cell carcinomas from the cancer genome atlas. Mol Cancer Res. 2016;14(7):589–98.PubMedPubMedCentral
48.
49.
Chakraborty S, Balan M, Sabarwal A, Choueiri TK, Pal S. Metabolic reprogramming in renal cancer: events of a metabolic disease. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188559.PubMedPubMedCentral
50.
Wettersten HI, et al. Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis. Cancer Res. 2015;75(12):2541–52.PubMedPubMedCentral
51.
Abu Aboud O, et al. Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging. Cancer Res. 2017;77(23):6746–58.PubMed
52.
Horiguchi A, Asano T, Asano T, Ito K, Sumitomo M, Hayakawa M. Fatty acid synthase over expression is an indicator of tumor aggressiveness and poor prognosis in renal cell carcinoma. J Urol. 2008;180(3):1137–40.PubMed
53.
Chung KT, Gadupudi GS. Possible roles of excess tryptophan metabolites in cancer. Environ Mol Mutagen. 2011;52(2):81–104.PubMed
54.
Kim K, Taylor SL, Ganti S, Guo L, Osier MV, Weiss RH. Urine metabolomic analysis identifies potential biomarkers and pathogenic pathways in kidney cancer. OMICS. 2011;15(5):293–303.PubMedPubMedCentral
55.
Ganti S, et al. Kidney tumor biomarkers revealed by simultaneous multiple matrix metabolomics analysis. Cancer Res. 2012;72(14):3471–9.PubMedPubMedCentral
56.
Yoon C-Y, et al. Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int J Cancer. 2007;120(4):897–905.PubMed
57.
Felipe-Abrio B, Verdugo-Sivianes EM, Carnero A. c-MYB- and PGC1a-dependent metabolic switch induced by MYBBP1A loss in renal cancer. Mol Oncol. 2019;13(7):1519–33.PubMedPubMedCentral
58.
59.
Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137(3):413–31.PubMed
60.
Tomasini R, et al. TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity. J Biol Chem. 2003;278(39):37722–9.PubMed
61.
Lu X, Nannenga B, Donehower LA. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 2005;19(10):1162–74.PubMedPubMedCentral
62.
Marchenko ND, Wolff S, Erster S, Becker K, Moll UM. Monoubiquitylation promotes mitochondrial p53 translocation. Embo j. 2007;26(4):923–34.PubMedPubMedCentral
63.
Wu H, Leng RP. UBE4B, a ubiquitin chain assembly factor, is required for MDM2-mediated p53 polyubiquitination and degradation. Cell Cycle. 2011;10(12):1912–5.PubMedPubMedCentral
64.
Ringshausen I, O’Shea CC, Finch AJ, Swigart LB, Evan GI. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell. 2006;10(6):501–14.PubMed
65.
Gurova KV, Hill JE, Razorenova OV, Chumakov PM, Gudkov AV. p53 pathway in renal cell carcinoma is repressed by a dominant mechanism. Cancer Res. 2004;64(6):1951–8.PubMed
66.
Wu H, et al. mTOR activation initiates renal cell carcinoma development by coordinating ERK and p38MAPK. Cancer Res. 2021;81(12):3174–86.PubMed
67.
Kang JH, et al. Renal cell carcinoma escapes death by p53 depletion through transglutaminase 2-chaperoned autophagy. Cell Death Dis. 2016;7(3):2163.
68.
Zhang H, et al. p53β: a new prognostic marker for patients with clear-cell renal cell carcinoma from 5.3 years of median follow-up. Carcinogenesis. 2018;39(3):368–74.PubMed
69.
Song W, et al. Expression of p53isoforms in renal cell carcinoma. Chin Med J. 2009;122(08):921–6.PubMed
70.
Miricescu D, et al. PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review). Exp Ther Med. 2021;21(5):540.PubMedPubMedCentral
71.
Sato Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45(8):860–7.PubMed
72.
Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007;12(2):104–7.PubMed
73.
74.
Baba M, et al. Loss of von Hippel-Lindau protein causes cell density dependent deregulation of CyclinD1 expression through hypoxia-inducible factor. Oncogene. 2003;22(18):2728–38.PubMed
75.
Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004;24(1):200–16.PubMedPubMedCentral
76.
Schödel J, et al. Hypoxia, hypoxia-inducible transcription factors, and renal cancer. Eur Urol. 2016;69(4):646–57.PubMed
77.
Hudson CC, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22(20):7004–14.PubMedPubMedCentral
78.
Koul H, et al. Molecular aspects of renal cell carcinoma: a review. Am J Cancer Res. 2011;1(2):240–54.PubMed
79.
Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruïne AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221(2):125–38.PubMed
80.
Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142(2):164–75.PubMed
81.
Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal. 2009;21(5):656–64.PubMedPubMedCentral
82.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101.PubMed
83.
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87.PubMedPubMedCentral
84.
Ilha J, do Espírito-Santo CC, do Freitas GR. mTOR signaling pathway and protein synthesis: from training to aging and muscle autophagy. Adv Exp Med Biol. 2018;1088:139–51.PubMed
85.
86.
Zhang J, Yu XH, Yan YG, Wang C, Wang WJ. PI3K/Akt signaling in osteosarcoma. Clin Chim Acta. 2015;444:182–92.PubMed
87.
Gao M, et al. Site-specific activation of AKT protects cells from death induced by glucose deprivation. Oncogene. 2014;33(6):745–55.PubMed
88.
Kumar A, Kumari N, Gupta V, Prasad R. Renal cell carcinoma: molecular aspects. Indian J Clin Biochem. 2018;33(3):246–54.PubMed
89.
Hers I, Vincent EE, Tavaré JM. Akt signalling in health and disease. Cell Signal. 2011;23(10):1515–27.PubMed
90.
Neshat MS, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98(18):10314–9.PubMedPubMedCentral
91.
92.
Lin A, Piao HL, Zhuang L, Sarbassov dos D, Ma L, Gan B. FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway. Cancer Res. 2014;74(6):1682–93.PubMedPubMedCentral
93.
Cox MA, et al. Beyond neurotransmission: acetylcholine in immunity and inflammation. J Intern Med. 2020;287(2):120–33.PubMed
94.
Tie P, Cheng J, Xue MX, Yin J, Fu G, Duan WL. SLC18A3 promoted renal cancer development through acetylcholine/cAMP signaling. Am J Cancer Res. 2022;12(9):4279–89.PubMedPubMedCentral
95.
Wang X, et al. Decrease of phosphorylated proto-oncogene CREB at Ser 133 site inhibits growth and metastatic activity of renal cell cancer. Expert Opin Ther Targets. 2015;19(7):985–95.PubMed
96.
Wang X, et al. Cyclic AMP responsive element-binding protein induces metastatic renal cell carcinoma by mediating the expression of matrix metallopeptidase-2/9 and proteins associated with epithelial-mesenchymal transition. Mol Med Rep. 2017;15(6):4191–8.PubMed
97.
Naviglio S, et al. Protein kinase A as a biological target in cancer therapy. Expert Opin Ther Targets. 2009;13(1):83–92.PubMed
98.
Friedrich M, et al. CREB1 is affected by the microRNAs miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p and correlates with adverse clinicopathological features in renal cell carcinoma. Sci Rep. 2020;10(1):6499.PubMedPubMedCentral
99.
Ahmed MB, Alghamdi AAA, Islam SU, Lee JS, Lee YS. cAMP signaling in cancer: a PKA-CREB and EPAC-centric approach. Cells. 2022;11(13):2020.PubMedPubMedCentral
100.
Hanusek K, Rybicka B, Popławski P, Adamiok-Ostrowska A, Głuchowska K, Piekiełko-Witkowska A, Bogusławska J. TGFβ1 affects the renal cancer miRNome and regulates tumor cells proliferation. Int J Mol Med. 2022;49(4):1–4
101.
Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Development. 2009;136(22):3699–714.PubMed
102.
Boguslawska J, Kryst P, Poletajew S, Piekielko-Witkowska A. TGF-β and microRNA interplay in genitourinary cancers. Cells. 2019;8(12):1619.PubMedPubMedCentral
103.
Boström AK, Lindgren D, Johansson ME, Axelson H. Effects of TGF-β signaling in clear cell renal cell carcinoma cells. Biochem Biophys Res Commun. 2013;435(1):126–33.PubMed
104.
Bao JM, et al. SPARC is a key mediator of TGF-β-induced renal cancer metastasis. J Cell Physiol. 2021;236(3):1926–38.PubMed
105.
Garcia JA, Cowey CL, Godley PA. Renal cell carcinoma. Curr Opin Oncol. 2009;21(3):266–71.PubMed
106.
Sültmann H, et al. Gene expression in kidney cancer is associated with cytogenetic abnormalities, metastasis formation, and patient survival. Clin Cancer Res. 2005;11(2 Pt 1):646–55.PubMed
107.
Yao M, et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst. 2002;94(20):1569–75.PubMed
108.
Mickley A, Kovaleva O, Kzhyshkowska J, Gratchev A. Molecular and immunologic markers of kidney cancer-potential applications in predictive, preventive and personalized medicine. Epma j. 2015;6:20.PubMedPubMedCentral
109.
Daugan MV, et al. Complement C1s and C4d as prognostic biomarkers in renal cancer: emergence of noncanonical functions of C1s. Cancer Immunol Res. 2021;9(8):891–908.PubMed
110.
Roumenina LT, et al. Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth. Cancer Immunol Res. 2019;7(7):1091–105.PubMed
111.
Ding YL, Sun SF, Zhao GL. COL5A2 as a potential clinical biomarker for gastric cancer and renal metastasis. Medicine (Baltimore). 2021;100(7):e24561.PubMed
112.
Zhang F, et al. HJURP is a prognostic biomarker for clear cell renal cell carcinoma and is linked to immune infiltration. Int Immunopharmacol. 2021;99:107899.PubMed
113.
Caliò A, Brunelli M, Gobbo S, Argani P, Munari E, Netto G, Martignoni G, Cathepsin K. A novel diagnostic and predictive biomarker for renal tumors. Cancers. 2021;13(10):2441.PubMedPubMedCentral
114.
Arance E, et al. Determination of exosome mitochondrial DNA as a biomarker of renal cancer aggressiveness. Cancers Basel. 2021;14(1):199.PubMedPubMedCentral
115.
Li F, Aljahdali IAM, Zhang R, Nastiuk KL, Krolewski JJ, Ling X. Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma. J Exp Clin Cancer Res. 2021;40(1):254.PubMedPubMedCentral
116.
Gebbia V, et al. Stereotactic radiotherapy for the treatment of patients with oligo-progressive metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitor: data from the real world. Anticancer Res. 2020;40(12):7037–43.PubMed
117.
Schmidt AL, Tabakin AL, Singer EA, Choueiri TK, McKay RR. Next steps: sequencing therapies in metastatic kidney cancer in the contemporary era. Am Soc Clin Oncol Educ Book. 2021;41:1–11.PubMed
118.
Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol. 1969;101(3):297–301.PubMed
119.
Permpongkosol S, Bagga HS, Romero FR, Sroka M, Jarrett TW, Kavoussi LR. Laparoscopic versus open partial nephrectomy for the treatment of pathological T1N0M0 renal cell carcinoma: a 5-year survival rate. J Urol. 2006;176(5):1984–8 (discussion 1988-9).PubMed
120.
Kyllo RL, et al. Prospective multi-center study of oncologic outcomes of robot-assisted partial nephrectomy for pT1 renal cell carcinoma. BMC Urol. 2012;12:11.PubMedPubMedCentral
121.
Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966–70.PubMed
122.
Flanigan RC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655–9.PubMed
123.
Krabbe LM, Bagrodia A, Margulis V, Wood CG. Surgical management of renal cell carcinoma. Semin Intervent Radiol. 2014;31(1):27–32.PubMedPubMedCentral
124.
Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006;28(11):1779–802.PubMed
125.
Mattei J, da Silva RD, Sehrt D, Molina WR, Kim FJ. Targeted therapy in metastatic renal carcinoma. Cancer Lett. 2014;343(2):156–60.PubMed
126.
Huang JJ, Hsieh JJ. The therapeutic landscape of renal cell carcinoma: from the dark age to the golden age. Semin Nephrol. 2020;40(1):28–41.PubMedPubMedCentral
127.
Rizzo M, Porta C. Sunitinib in the treatment of renal cell carcinoma: an update on recent evidence. Ther Adv Urol. 2017;9(8):195–207.PubMedPubMedCentral
128.
Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.PubMed
129.
Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884–96.PubMed
130.
Gan HK, Seruga B, Knox JJ. Sunitinib in solid tumors. Expert Opin Invest Drugs. 2009;18(6):821–34.
131.
Welsh SJ, Fife K. Pazopanib for the treatment of renal cell carcinoma. Future Oncol. 2015;11(8):1169–79.PubMed
132.
Zivi A, Cerbone L, Recine F, Sternberg CN. Safety and tolerability of pazopanib in the treatment of renal cell carcinoma. Expert Opin Drug Saf. 2012;11(5):851–9.PubMed
133.
Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D. 2011;11(2):113–26.PubMed
134.
Keating GM. Axitinib: a review in advanced renal cell carcinoma. Drugs. 2015;75(16):1903–13.PubMed
135.
Suyama K, Iwase H. Lenvatinib: a promising molecular targeted agent for multiple cancers. Cancer Control. 2018;25(1):1073274818789361.PubMedPubMedCentral
136.
Yakes FM, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308.PubMed
137.
Abdelaziz A, Vaishampayan U. Cabozantinib for renal cell carcinoma: current and future paradigms. Curr Treat Opt Oncol. 2017;18(3):18.
138.
Negrier S, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d’Immunothérapie. N Engl J Med. 1998;338(18):1272–8.PubMed
139.
140.
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–96.PubMed
141.
McDermott DF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23(1):133–41.PubMed
142.
Yang JC, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21(16):3127–32.PubMed
143.
Kawashima H, Kimura Y. Present and future perspectives on immunotherapy for advanced renal cell carcinoma: Going to the core or beating around the bush? J Kidney Cancer VHL. 2015;2(2):55–63.PubMedPubMedCentral
144.
145.
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86.PubMedPubMedCentral
146.
Mohsenzadegan M, et al. The potential of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) in designing novel immunotherapy for bladder cancer. Endocr Metab Immune Disord Drug Targets. 2021;21(12):2131–46.PubMed
147.
Kim MC, et al. Updates on immunotherapy and immune landscape in renal clear cell carcinoma. Cancers (Basel). 2021;13(22):5856.PubMed
148.
Sun C, et al. CD133 expression in renal cell carcinoma (RCC) is correlated with nuclear hypoxia-inducing factor 1α (HIF-1α). J Cancer Res Clin Oncol. 2012;138(10):1619–24.PubMed
149.
Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12(10):2575–87.PubMedPubMedCentral
150.
151.
Brahmer JR, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2023;41(4):715–23.PubMed
152.
Liebl MC, Hofmann TG. Identification of responders to immune checkpoint therapy: which biomarkers have the highest value? J Eur Acad Dermatol Venereol. 2019;33(Suppl 8):52–6.PubMed
153.
Rini BI, et al. Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–27.PubMed
154.
Rizvi NA, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65.PubMedPubMedCentral
155.
De Sousa Linhares A, et al. Therapeutic PD-L1 antibodies are more effective than PD-1 antibodies in blocking PD-1/PD-L1 signaling. Sci Rep. 2019;9(1):11472.PubMedPubMedCentral
156.
Herbst RS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.PubMedPubMedCentral
157.
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9.PubMed
158.
Doroshow DB, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18(6):345–62.PubMed
159.
Simeone JC, Nordstrom BL, Patel K, Klein AB. Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting. Future Oncol. 2019;15(30):3491–502.PubMed
160.
Stewart R, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3(9):1052–62.PubMed
161.
Massard C, et al. Safety and efficacy of Durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25.PubMedPubMedCentral
162.
Collins JM, Gulley JL. Product review: avelumab, an anti-PD-L1 antibody. Hum Vaccin Immunother. 2019;15(4):891–908.PubMed
163.
Choueiri TK, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451–60.PubMed
164.
Larkin JMG, et al. Avelumab (MSB0010718C; anti-PD-L1) in combination with axitinib as first-line treatment for patients with advanced renal cell carcinoma. J Clin Oncol. 2016;34(15_suppl):4580.
165.
Suárez C, et al. Phase II study investigating the safety and efficacy of Savolitinib and Durvalumab in metastatic papillary renal cancer (CALYPSO). J Clin Oncol. 2023;41(14):2493–502.PubMed
166.
Voss MH, et al. A randomized phase II study of MEDI0680 in Combination with Durvalumab versus Nivolumab monotherapy in patients with advanced or metastatic clear-cell renal cell carcinoma. Clin Cancer Res. 2022;28(14):3032–41.PubMedPubMedCentral
167.
Escudier B, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28(13):2144–50.PubMed
168.
Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.PubMed
169.
Rini BI, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27(27):4462–8.PubMed
170.
171.
Choueiri TK, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31(8):1030–9.PubMed
172.
Syn NL, Teng MWL, Mok TSK, Soo RA. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 2017;18(12):e731–41.PubMed
173.
Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561–84.PubMed
174.
Brunet JF, et al. A new member of the immunoglobulin superfamily–CTLA-4. Nature. 1987;328(6127):267–70.PubMed
175.
Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229(1):12–26.PubMedPubMedCentral
176.
Linsley PS, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257(5071):792–5.PubMed
177.
Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16(1):23–35.PubMed
178.
Mullard A. FDA approves first immunotherapy combo. Nat Rev Drug Discov. 2015;14(11):739–739.
179.
Powderly J, et al. CA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study. Ann Oncol. 2017;28:v405–6.
180.
Klapper JA, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113(2):293–301.PubMed
181.
Charych DH, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22(3):680–90.PubMed
182.
Diab A, et al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. J Clin Oncol. 2018;36(15_suppl):3006.
183.
Tugues S, et al. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22(2):237–46.PubMed
184.
Janiszewska AD, Poletajew S, Wasiutyński A. Spontaneous regression of renal cell carcinoma. Contemp Oncol (Pozn). 2013;17(2):123–7.PubMed
185.
Choueiri TK, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115–25.PubMedPubMedCentral
186.
Gore ME, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10(8):757–63.PubMed
187.
Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(Suppl 1):S55–7.PubMed
188.
Fishman M, et al. Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIM(SM) registry. J Immunother Cancer. 2019;7(1):84.PubMedPubMedCentral
189.
Rini BI, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404–15.PubMed
190.
Motzer RJ, et al. NCCN Guidelines Insights: kidney cancer, version 2.2020. J Natl Compr Cancer Netw. 2019;17(11):1278–85.
191.
Albiges L, et al. Updated European Association of Urology Guidelines on renal cell carcinoma: immune checkpoint inhibition is the new backbone in first-line treatment of metastatic clear-cell renal cell carcinoma. Eur Urol. 2019;76(2):151–6.PubMed
192.
Motzer RJ, et al. Avelumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–15.PubMedPubMedCentral
193.
Motzer RJ, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888–98.PubMedPubMedCentral
194.
Motzer RJ, et al. Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90.PubMedPubMedCentral
195.
Escudier B, Barthelemy P, Ravaud A, Negrier S, Needle MN, Albiges L. Tivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36(6_suppl):618.
196.
Amin A, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(15_suppl):5010.
197.
Chowdhury S, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2017;35(15_suppl):4506.
198.
Meza L, Govindarajan A, Feng M, Pal SK. Live bacterial supplementation for improving treatment response in metastatic renal cell carcinoma. Clin Transl Med. 2022;12(7):e948.PubMedPubMedCentral
199.
Dizman N, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022;28(4):704–12.PubMedPubMedCentral
200.
Derosa L, et al. Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. Eur Urol. 2020;78(2):195–206.PubMed
201.
Owens JA, et al. Lactobacillus rhamnosus GG orchestrates an antitumor immune response. Cell Mol Gastroenterol Hepatol. 2021;12(4):1311–27.PubMedPubMedCentral
202.
He Y, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8(+) T cell immunity. Cell Metab. 2021;33(5):988-1000.e7.PubMed
203.
Routy B, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.PubMed
204.
Cuvillier O. The therapeutic potential of HIF-2 antagonism in renal cell carcinoma. Transl Androl Urol. 2017;6(1):131–3.PubMedPubMedCentral
205.
Lee C-H, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial. J Clin Oncol. 2021;39(15):4509.
206.
Jonasch E, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020;38(15_Suppl):5003.
207.
Pal SK, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185–95.PubMed
208.
Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer RJ. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020;38(6_Suppl):767.
209.
Zhang T, et al. PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol. 2021;39(6_Suppl):366.
210.
Tannir NM, et al. PIVOT-09: A phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator’s choice) in patients with previously untreated advanced renal cell carcinoma (RCC). J Clin Oncol. 2020;38(6_Suppl):763.
211.
Koshkin VS, Rini BI. Emerging therapeutics in refractory renal cell carcinoma. Expert Opin Pharmacother. 2016;17(9):1225–32.PubMed
212.
213.
Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67(6):507–24.PubMed
Metadata
Title
Molecular insight into renal cancer and latest therapeutic approaches to tackle it: an updated review
Authors
Reshma Murali
Abilash Valsala Gopalakrishnan
Publication date
13-11-2023
Publisher
Springer US
Published in
Medical Oncology / Issue 12/2023
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-023-02225-0

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