PARP Inhibitors in Prostate Cancer-the Preclinical Rationale and Current Clinical Development

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

Simple SummaryProstate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate cancer and correlates with the aggressiveness of the disease. PSMA is a promising target for imaging and therapeutics in prostate cancer patients validated in prospective trials. However, the role of PSMA in prostate cancer progression is poorly understood. In this review, we discuss the biology and scientific rationale behind the use of PSMA and other targets in the detection and theranostics of metastatic prostate cancer.Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer

Den genomsnittliga effektiva dosen hos finländarna 2018

I den här rapporten uppdateras uppgifterna om den genomsnittliga effektiva dosen finländarna får årligen. Finländare exponeras för joniserande strålning från både naturliga och konstgjorda källor. År 2018 uppgick finländarnas genomsnittliga effektiva till 5,9 millisievert. Två tredjedelar av den här stråldosen, 4 mSv, härstammar från radon i inomhusluften. Cirka 1,1 mSv av finländarnas årliga effektiva dos beror på naturens bakgrundsstrålning (annat än radon i inomhusluften). Medicinsk användning av strålning orsakar finländare i genomsnitt en årlig effektiv dos på 0,76 mSv

Suomalaisten keskimääräinen efektiivinen annos vuonna 2018

Tässä raportissa päivitetään tiedot suomalaisten vuosittain saamasta keskimääräisestä efektiivisestä annoksesta. Suomalaiset altistuvat niin luonnollisista kuin keinotekoisista lähteistä peräisin olevalle ionisoivalle säteilylle. Vuonna 2018 suomalaisten saama keskimääräinen efektiivinen annos oli 5,9 millisievertiä (mSv). Kaksi kolmasosaa tästä säteilyannoksesta, 4 mSv, on peräisin sisäilman radonista. Noin 1,1 mSv suomalaisten vuotuisesta efektiivisestä annoksesta aiheutuu luonnon taustasäteilystä (muu kuin sisäilman radon). Säteilyn lääketieteellinen käyttö aiheuttaa suomalaiselle keskimäärin 0,76 mSv vuotuisen efektiivisen annoksen

PARP Inhibitors in Prostate Cancer – The Preclinical Rationale and Current Clinical Development

Prostate cancer is the second most commonly diagnosed cancer type in men in the Western world. The majority of prostate cancer patients have a good prognosis, while some prostate cancers advance locally or metastasize. Metastatic disease is treated with either surgical or chemical castration, which can be combined with other therapies, such as chemotherapy. However, advanced prostate cancer usually progresses to the castration-resistant stage after a couple of years of androgen deprivation therapy. There are currently no curative treatments available for metastatic castration-resistant prostate cancer. Defects in genes associated with DNA damage response are found at higher frequency in metastatic castration-resistant prostate cancer when compared to prostate cancers with better prognosis. Up to 20 % of metastatic castration-resistant prostate cancers harbor somatic or germline aberrations in BRCA2, BRCA1 or ATM genes. Mutations in these genes are associated with more aggressive disease. Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme that becomes necessary for the survival and functioning of the cancer cell after obtaining aberrations in specific DNA repair genes, such as BRCA. FDA has approved PARP inhibitor therapies in the treatment of ovarian and breast cancer. PARP inhibitors are currently being studied in prostate cancer trials. This systematic review article aims to acquaint the reader with the current state of clinical studies of PARP inhibitor-related therapies in prostate cancer and explains at the molecular level the basis of the therapies used in the trials. Ongoing clinical trials and the results from completed trials of PARP inhibitors in prostate cancer are presented as tables. The data for the table presenting results from published trials was acquired by conducting a systematic search in the Pubmed and Web of Science databases using specific search terms. The data for the ongoing trials was acquired by a systematic search conducted in the ClinicalTrials.gov -website using the specific parameters. There are currently 12 published results from clinical trials using PARP inhibitors in prostate cancer, 4 of which are phase two studies. Currently there are no published phase three studies available. PARP inhibitor study data from ClinicalTrials.gov database contained 11 ongoing monotherapy studies and 29 ongoing combination therapies. The article describes in detail the biological rationale behind the use of PARP inhibitors as monotherapy or in combination with other treatments. Novel therapies for aggressive prostate cancer with specific genetic aberrations detected may include drugs targeting DNA damage response in the coming years.Eturauhassyöpä on länsimaissa toiseksi yleisin miesten syöpä. Suurimmalla osalla potilaista tauti on hyväennusteinen, mutta osalla tauti etenee paikallisesti tai metastasoi. Levinneen taudin hoitona on joko kirurginen tai lääkkeellinen kastraatio, johon voidaan yhdistää muita hoitoja, kuten sytostaattihoito. Levinnyt eturauhassyöpä kuitenkin muuttuu kastraatioresistentiksi yleensä kahden vuoden kuluessa hormonaalisen hoidon alkamisesta. Levinneeseen kastraatioresistenttiin eturauhassyöpään ei ole kuratiivista hoitoa. Virheitä DNA:n korjausta ohjaavissa geeneissä on todettavissa huomattavasti useammin levinneessä kastraatioresistentissä taudissa verrattaessa hyväennusteiseen eturauhassyöpään. Perinnöllisiä tai hankinnaisia geenivirheitä BRCA2-, BRCA1- tai ATM-geeneissä on todettavissa jopa 20 %:ssa levinneistä kastraatioresistenteistä eturauhassyövistä. Mutaatiot näissä geeneissä ovat yhteydessä aggressiivisempaan tautiin. PARP on DNA:n korjausentsyymi, josta tulee eturauhassyöpäsolussa välttämätön sen toiminnan ja selviytymisen kannalta tiettyjen DNA:n korjaamiseen liittyvien geenivirheiden ilmaantumisen jälkeen. PARP-estäjiä on hyväksytty Yhdysvalloissa lääkkeeksi munasarja- ja rintasyövän hoidossa, ja PARP-estäjiä tutkitaan aktiivisesti eturauhassyövän hoidossa. Artikkelissa esitellään taulukossa tämänhetkiset käynnissä olevat kliiniset tutkimukset PARP-estäjistä eturauhassyövän hoidossa, aikaisempien kliinisten tutkimusten tulokset ja lisäksi kuvataan hoitojen biologinen tausta. Artikkelin tarkoituksena on tutustuttaa lukija aggressiivisen eturauhassyövän lääkehoidon kehittämisen nykytilaan PARP-estäjien osalta. Samalla artikkelissa selvitetään molekyylitasolla kliinisten tutkimusten ja hoitojen perusta. Aineisto aikaisempia tutkimuksia kuvaavaan taulukkoon haettiin systemaattisesti Pubmed- ja Web of Science -tietokannoista hakusanoilla taulukon yhteydessä ilmoitetuilla hakutermeillä. Aineisto käynnissä olevista kliinisistä tutkimuksista kerättiin haulla ClinicalTrials.gov-sivustolta taulukon yhteydessä ilmoitetuilla hakutermeillä. PARP-estäjistä eturauhassyövän hoidossa on julkaistu 12 kliinistä tutkimusta, joista 4 ovat toisen faasin tutkimuksia. Kolmannen vaiheen tutkimuksista ei ole vielä valmiita julkaistuja tuloksia. ClinicalTrials.gov-haku tuotti aineiston, jossa on 11 käynnissä olevaa monoterapiatutkimusta ja lisäksi 29 tutkimusta, joissa PARP-estäjät ovat osana yhdistelmähoitoa. Tulevaisuudessa aggressiivisen eturauhassyövän hoidossa saatetaan tulla hyödyntämään DNA:n korjaukseen vaikuttavia lääkehoitoja potilailla, joilla on tunnistettu tiettyjä geenivirheitä

PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors