Abstract
Simple SummaryMetastatic prostate cancer is incurable and lethal. Tumor growth is initially reduced by radiation, surgery, or hormone therapy and later, by pairing them with chemotherapy for advanced cancer. Recent innovations have helped to develop prescription drugs against certain prostate cancer types, showing gene alterations that prevent the repair of damaged DNA or activate the body’s anti-cancer natural immune defense. A panel of genes has been identified whose cancer genome alterations may predict whether non-metastatic prostate cancer would go on to metastasize. The activity of these genes may help to guide treatment decision for non-metastatic cancer with the choice for non-aggressive versus debilitating aggressive options. The probing of prostate cancer genome has uncovered hormonal abnormalities and genome changes specific to individual patients and studies are revealing how these changes can lead to treatment failure. The discovery of new druggable vulnerabilities of the cancer cells has presented opportunities to develop precision treatments of metastatic prostate cancer tailored to individual patients.Organ-confined prostate cancer of low-grade histopathology is managed with radiation, surgery, active surveillance, or watchful waiting and exhibits a 5-year overall survival (OS) of 95%, while metastatic prostate cancer (PCa) is incurable, holding a 5-year OS of 30%. Treatment options for advanced PCa—metastatic and non-metastatic—include hormone therapy that inactivates androgen receptor (AR) signaling, chemotherapy and genome-targeted therapy entailing synthetic lethality of tumor cells exhibiting aberrant DNA damage response, and immune checkpoint inhibition (ICI), which suppresses tumors with genomic microsatellite instability and/or deficient mismatch repair. Cancer genome sequencing uncovered novel somatic and germline mutations, while mechanistic studies are revealing their pathological consequences. A microRNA has shown biomarker potential for stratifying patients who may benefit from angiogenesis inhibition prior to ICI. A 22-gene expression signature may select high-risk localized PCa, which would not additionally benefit from post-radiation hormone therapy. We present an up-to-date review of the molecular and therapeutic aspects of PCa, highlight genomic alterations leading to AR upregulation and discuss AR-degrading molecules as promising anti-AR therapeutics. New biomarkers and druggable targets are shaping innovative intervention strategies against high-risk localized and metastatic PCa, including AR-independent small cell-neuroendocrine carcinoma, while presenting individualized treatment opportunities through improved design and precision targeting.
Highlights
As the second most common male cancer worldwide, only to lung cancer, prostate cancer affects roughly 1.3 million people and kills more than 360,000 people annually
We summarize progress in the molecular and genomic characterization of various stages of prostate cancer (PCa)—from high-risk localized and metastatic disease to neuroendocrine carcinoma, which is a highly aggressive form of advanced PCa—describe how insights gleaned from ongoing studies are revealing new vulnerabilities of cancer cells, and highlight several potential targets that are being pursued for future interventions tailored to individual patients
Innovations in managing metastatic castrationresistant prostate cancer (mCRPC), including small cell/neuroendocrine carcinoma variants, are facilitated by a growing list of actionable genomic changes revealed by next-generation genome sequencing
Summary
As the second most common male cancer worldwide, only to lung cancer, prostate cancer affects roughly 1.3 million people and kills more than 360,000 people annually. Cytosolic AR, when bound to androgens at the ligand-binding domain (LBD) of the receptor, dissociates from multiple AR-interacting proteins, including heat shock proteins hsp and hsp, undergoes a conformational change that exposes a nuclear localization signal and facilitates transport of the androgen/AR complex to the nucleus [7,8] Chromatin recruitment of this complex to androgen response element(s) in target genes and receptor interaction with coregulators lead to transcriptional induction or repression of AR-regulated genes (Figure 1). Recent insights into genome alterations in prostate cancer that impact signaling pathways beyond the androgen receptor axis, subtypes of early stage and advanced PCa, and the dynamics of tumor-promoting and tumor-suppressive effects of immune cells are revealing. S1i.mSpimlifipeldifsicehdemscahfeomr AaRfo-mr eAdRia-tmedetdarigaetet dgetnaergtreatngscernipetitornaanlsrcersippotnisoen. aDlHreTs-bpoounnsde.ADRHT-boun didssisoscoiactieastfersomfrochmapcehraonpeerporonteeipnsro(HteSinPss)(aHndSPosth) earnindteortahcetirnginptreortaecintisn, gexpporositneginAsR, e’sxnpuocsleinarg AR’s n lolcoacliazlaitzioantisoingnsailganndalfaacnilidtatfiancgilrietcaetpintogr’srencuecpletaorri’mspnourtc. lUeparonimrecprourittm. eUnpt toonanrdercorgueintmreespnotntsoe androg elsepmoennstseoeflAemR etanrtgsetogfeAneRs, ttahregheotrgmeonnees-b, othunedhAoRrminotnerea-cbtos uwnitdh vAaRrioiunstecroarcegtsulwatiotrhs lveaardiionugs coregu toletaardgientggetonetatrragnestcgriepntieontraal nresscproipntsieo.nAalnraensdproongseen.-iAndneapnenddreongtepna-tihnwdeaypemnadyenaltsopadtrhivweaAyRmay acAtivRataicotnivaantdiointsacnydtopitlsascmytotopnlauscmleutsotnrauncslfeeur ssutrbasenqsuferntsutobAseRqupehnostpthooAryRlatpiohnosbpyhvoarryiolautsion by v kiknianseass.eDs.HDT:H5αT-:d5ihαy-ddriohteysdtorsoteterosntoe;sHteSrPosn: eh;eHatSshPosc:khperaottesihnso;cFkKBpPro52t:efionrss;kFolKinB-bPi5n2d:infgorpsrkotoeliinn-bindin 52t;eIiLn65-R2:;iInLte6r-lReu: kininte6rrleecuekpitnor;6RrTeKce: pretcoerp;toRrTtKyr:orseinceepkitnoarsety. rosine kinase
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