Uncovering the genetic landscape driving castration-resistant prostate cancer

Martin, Timothy J.; Peer, Cody J.; Figg, William D.

doi:10.4161/cbt.24426

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…55 Other genetic factors, including certain gene mutations that regulate cell survival, proliferation, or apoptosis, affect development of CRPC/mCRPC and response to treatment. 56 Studies have demonstrated that several key genetic factors may correlate with risk and timing of progression to CRPC. For example, pathogenic germline variants in cancer-susceptibility genes, including ATM, ATR, BRCA2, FANCL, MSR1, MUTYH, RB1, TSHR, and WRN, have been observed in patients with mCRPC.…”

Section: Hereditary Genetic Factors/mutationsmentioning

confidence: 99%

Resetting the Bar of Castration Resistance – Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer

Shore

Morgans

Ryan

2021

Clinical Genitourinary Cancer

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This review discusses impact of advancements in biologic understanding of prostate cancer (PCa) on definition and diagnosis of castration-resistant PCa (CRPC), predictive factors for progression to CRPC and treatment strategies. More sensitive assays confirm that bilateral orchiectomy reduces serum testosterone (T) closer to < 20 ng/dL than < 50 ng/dL, and evidence suggests that achieving T < 20 ng/dL improves outcomes and delays CRPC emergence. Regular T assessments will evaluate whether T is adequately suppressed in the setting of potential progression to CRPC, given that late dosing may result in T escape. More advanced imaging modalities and biomarker assays allow earlier detection of disease progression. Predictive factors for progression to CRPC include Gleason grade, extent of metastatic spread, germline hereditary factors such as gene mutations affecting androgen receptor amplification or DNA repair deficiency mutations, prostate-specific antigen kinetics, and biomarker analyses. Treatment options for CRPC have expanded beyond androgen deprivation therapy to include therapies that suppress T or inhibit its activity through varying mechanisms. Future directions include therapies with novel biological targets, drug combinations and personalized treatments. Advanced PCa management aims to delay progression to CRPC and prolong survival. With redefinition of castration and advancements in understanding of the biology of disease progression, diagnosis and treatment strategies should be re-evaluated. Definition of CRPC could be updated to reflect the T < 20 ng/dL requirement as this is a 'true' castrate level and may improve outcomes. It is important that androgen deprivation therapy as foundational therapy is continued even as new CRPC therapies are introduced.

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Section: Hereditary Genetic Factors/mutationsmentioning

confidence: 99%

Resetting the Bar of Castration Resistance – Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer

Shore

Morgans

Ryan

2021

Clinical Genitourinary Cancer

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“…Известно, что гены, влияющие на активацию или амплификацию АР, способствуют прогрессированию КРРПЖ [50]. Другие генетические факторы, включая определенные мутации генов, регулирующих выживание клеток, пролиферацию или апоптоз, влияют на развитие КРРПЖ, в т. ч. метастатического, и ответ на лечение [51]. Исследования показали, что несколько ключевых генетических факторов могут коррелировать с риском и сроками прогрессирования КРРПЖ.…”

Section: наследственные генетические факторы/мутацииunclassified

The castration level of testosterone and hormonal resistance of prostate cancer in androgen deprivation therapy

Русаков

Грицкевич²,

Baitman³

et al. 2020

Medicinskij sovet

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This review is dedicated to the impact of modern achievements on the definition and diagnostics of castration-resistant prostate cancer (PCa) (CRPC), prognostic factors for its progression, and treatment strategies.It was proven with new sensitive methods of diagnostics that surgical castration (CS) decreases serum testosterone (T) levels to < 20 ng/dL, while achieving T < 20 ng/dL improves outcomes and delays the development of CRPC. Regular assessment of the T level makes it possible to understand whether this androgen is adequately suppressed in the setting of potential progression of CRPC, given that late dosing may lead to an increase in T level. Improved imaging techniques and biomarker analysis enable early detection of disease progression. Prognostically significant risk factors for CRPC progression include Gleason score, the extent of metastatic spread, hereditary characteristics such as gene mutations affecting androgen receptor (AR) amplification or DNA repair deficiency mutations, prostate-specific antigen (PSA) kinetics, and biomarker levels. Today, treatment options for CRPC have gone beyond androgen deprivation therapy (ADT) to include therapy that blocks T-synthesis and/or suppresses its activity through various mechanisms. Future directions include therapies using new biological targets, drug combinations and personalized therapies. It is necessary to assess the possible reasons for the difference in the pharmacodynamics and pharmacokinetics of androgendeprivation drugs, to study the features of the processes of destruction of drugs under the action of endogenous enzymes and resorption in the subcutaneous or muscle depot, which may cause the resistance to therapy.The aim of improved treatment and diagnostic options for PCa is to delay its progression to CRPC and to prolong patient survival. Rethinking of the castration concept and advances in understanding the biology of disease progression make it necessary to revise diagnostic and treatment strategies. ADT is a fundamental vector of treatment, and it should be continued even if some new ways of treatment for CRPC are introduced.

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“…But the most striking evidence for CHD1 inactivation is in prostate cancer, where it is deleted or mutated (Grasso et al 2012; Huang et al 2012; Liu et al 2012; Burkhardt et al 2013; Martin et al 2013; Blattner et al 2014; Gao et al 2014; Scott et al 2014; Tereshchenko et al 2014; Attard et al 2015; Fisher et al 2015; Sowalsky et al 2015). Indeed, homozygous deletion of CHD1 is the second most common genetic event in prostate cancer after PTEN deletion (Liu et al 2012).…”

Section: Subfamily I: Chd1 Chd2mentioning

confidence: 99%

“…Chromosome rearrangements that cause overexpression of ETS family members, most commonly translocations between the androgen-regulated gene TMPRSS2 and the ERG gene, are frequent in some types of prostate cancer (Clark and Cooper 2009). CHD1 lesions occur in ETS fusion-negative prostate cancer (Grasso et al 2012; Martin et al 2013; Tereshchenko et al 2014), indicating that the CHD1 status defines a unique prostate cancer subtype (Attard et al 2015; Fisher et al 2015). Whereas CHD1 mutation and ETS fusions are mutually exclusive, CHD1 inactivation co-occurs with speckle type PTB/POZ protein (SPOP) mutations (Blattner et al 2014) and MAP3K7 deletion (Rodrigues et al 2015), suggesting that these lesions cooperate with CHD1 loss to drive tumorigenesis in the prostate.…”

Section: Subfamily I: Chd1 Chd2mentioning

confidence: 99%

The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

Mills

2017

Cold Spring Harb Perspect Med

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A plethora of mutations in chromatin regulators in diverse human cancers is emerging, attesting to the pivotal role of chromatin dynamics in tumorigenesis. A recurrent theme is inactivation of the Chromodomain Helicase DNA-binding (CHD) family of proteins—ATP-dependent chromatin remodelers that govern the cellular machinery’s access to DNA, thereby controlling fundamental processes including transcription, proliferation, and DNA damage repair. This review highlights what is currently known about how genetic and epigenetic perturbation of CHD proteins and the pathways they regulate set the stage for cancer, providing new insight for designing more effective anti-cancer therapies.

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Uncovering the genetic landscape driving castration-resistant prostate cancer

Cited by 6 publications

References 10 publications

Resetting the Bar of Castration Resistance – Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer

Resetting the Bar of Castration Resistance – Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer

The castration level of testosterone and hormonal resistance of prostate cancer in androgen deprivation therapy

The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

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