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GENE:

CDK12 (Cyclin dependent kinase 12)

News alerts, weekly reports and conference planners

Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer. (PubMed, Clin Transl Med)

CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.

6 days ago

Journal • PARP Biomarker

CDK12 (Cyclin dependent kinase 12) • ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4)

IACS-010759

14d

Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer. (PubMed, Mol Cytogenet)

These data show that analysis of CDK12 alteration, in the context of MHC expression levels, and LOH status may offer improved predictive value for outcomes in this potentially actionable genomic subgroup of PCa. In addition, these findings highlight the need to explore novel therapeutic strategies to enhance MHC expression in CDK12-defective PCa to improve immunotherapy responses.

14 days ago

Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • CDK12 (Cyclin dependent kinase 12) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • IDO1 (Indoleamine 2,3-dioxygenase 1)

PD-L1 expression • CDK12 mutation • IDO1 expression

21d

Treatment patterns, clinical outcomes and gene mutation characteristics of hepatitis B virus-associated mantle cell lymphoma. (PubMed, Hematol Oncol)

The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens...Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.

21 days ago

Clinical data • Journal • Tumor mutational burden

TMB (Tumor Mutational Burden) • NF1 (Neurofibromin 1) • FGFR4 (Fibroblast growth factor receptor 4) • CDK12 (Cyclin dependent kinase 12) • PLCG2 (Phospholipase C Gamma 2) • FIP1L1 (Factor Interacting With PAPOLA And CPSF1) • JAK3 (Janus Kinase 3) • HDAC1 (Histone Deacetylase 1) • TP63 (Tumor protein 63) • SMAD2 (SMAD Family Member 2) • SMC1A (Structural Maintenance Of Chromosomes 1A)

BLM mutation • JAK3 mutation

Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • cyclophosphamide • vincristine

25d

Nivolumab + Docetaxel + ADT in mHSPC Patients With DDRD or Inflamed Tumors (clinicaltrials.gov)

P2; Recruiting --> Active, not recruiting

25 days ago

Combination therapy • Enrollment closed • Metastases

PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • ABRAXAS1 (Abraxas 1 BRCA1 A Complex Subunit 2) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)

PD-L1 expression • MSI-H/dMMR

OncoPanel™ Assay

Opdivo (nivolumab) • docetaxel • goserelin acetate • Firmagon (degarelix) • leuprolide acetate for depot suspension

25d

Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations. (PubMed, Clin Genitourin Cancer)

Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.

25 days ago

Clinical data • Journal • BRCA Biomarker • Metastases

BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12)

ATM mutation • CDK12 mutation

26d

Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes (clinicaltrials.gov)

P1, N=30, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

26 days ago

Enrollment open

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)

BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • RAD50 mutation • RAD51B mutation • BARD1 mutation • BLM mutation • FANCF mutation • MRE11A mutation • NBN mutation • FANCM mutation • RAD51 mutation

27d

ATRIUM: A Study of ATG-018 (ATR Inhibitor) Treatment in Patients With Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov)

P1, N=88, Recruiting, Antengene Discovery Limited | Trial primary completion date: Mar 2024 --> Jun 2024

27 days ago

Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)

TP53 mutation • FANCF mutation

ATG-018

INSPIRE: Ipilimumab With Nivolumab for Molecular-selected Patients With Castration-resistant Prostate Cancer (clinicaltrials.gov)

P2, N=69, Active, not recruiting, Radboud University Medical Center | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Feb 2026 | Trial primary completion date: Jan 2025 --> Aug 2024

1 month ago

Enrollment closed • Trial completion date • Trial primary completion date

TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12)

TMB-H

Opdivo (nivolumab) • Yervoy (ipilimumab)

Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies. (PubMed, Int J Cancer)

Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

1 month ago

Journal • Liquid biopsy • BRCA Biomarker • Biopsy

TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • CDK12 (Cyclin dependent kinase 12) • TMPRSS2 (Transmembrane serine protease 2)

BrUOG 360: A Study of Copanlisib Combined With Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov)

P1/2, N=13, Active, not recruiting, Brown University | Trial completion date: May 2024 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jan 2027

1 month ago

Trial completion date • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)

BRIP1 mutation

Rubraca (rucaparib) • Aliqopa (copanlisib)

CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer. (PubMed, Cancer Lett)

Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.

1 month ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • RAD51 (RAD51 Homolog A)

BRCA wild-type

Lynparza (olaparib) • cisplatin • gemcitabine • dinaciclib (MK-7965)

2ms

NIRADO: Basket Trial Exploring the Efficacy and Safety of the Combination of Niraparib and Dostarlimab (clinicaltrials.gov)

P2, N=51, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=112 --> 51 | Trial completion date: Mar 2027 --> Dec 2027 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Dec 2024

2 months ago

Enrollment change • Trial completion date • Trial suspension • Trial primary completion date • Pan tumor

HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • ARID1A (AT-rich interaction domain 1A) • PBRM1 (Polybromo 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • ARID2 (AT-Rich Interaction Domain 2) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • DRD (DNA Repair Deficiency)

HER-2 positive • HER-2 amplification • DDR • PBRM1 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • BARD1 mutation • NBN mutation • DRD

Zejula (niraparib) • Jemperli (dostarlimab-gxly)

2ms

ARIANES: Efficacy and Safety of the Combination of Rucaparib (PARP Inhibitor) and Atezolizumab (Anti-PD-L1 Antibody) in Patients With DNA Repair-deficient or Platinum-sensitive Solid Tumors (clinicaltrials.gov)

P2, N=130, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=1000 --> 130 | Trial primary completion date: Apr 2024 --> Dec 2024

2 months ago

Enrollment change • Trial primary completion date • Pan tumor

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • IL2 (Interleukin 2) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • DRD (DNA Repair Deficiency)

DDR • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • BARD1 mutation • NBN mutation • DRD

Tecentriq (atezolizumab) • Rubraca (rucaparib)

2ms

CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer. (PubMed, Sci Rep)

These findings establish CDK12 as a significant biological indicator of cancer diagnosis, prognosis, and immunotherapeutic targeting. Early surveillance and employment of CDK12 inhibitors, along with concomitant immunotherapy interventions, may enhance the clinical outcomes of cancer patients.

2 months ago

Journal • IO biomarker • Pan tumor • Immunomodulating

CDK12 (Cyclin dependent kinase 12)

CDK12 mutation

2ms

CHOMP: A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation (clinicaltrials.gov)

P2, N=30, Recruiting, VA Office of Research and Development | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

2 months ago

Trial completion date • Trial primary completion date • Checkpoint inhibition • Mismatch repair • Metastases

EGFR (Epidermal growth factor receptor) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • PMS1 (PMS1 protein homolog 1)

MSI-H/dMMR

Keytruda (pembrolizumab) • abiraterone acetate

2ms

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. (PubMed, Int J Biol Sci)

Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.

2 months ago

Journal

CDK12 (Cyclin dependent kinase 12)

CDK2 overexpression

cisplatin

2ms

Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis. (PubMed, J Clin Oncol)

In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.

2 months ago

Retrospective data • Journal • BRCA Biomarker • PARP Biomarker • Metastases

HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12)

2ms

Genomic landscape of circulating tumor DNA in cervical cancer in Asia: NCCH1905/A-TRAIN trial (AACR 2024)

Comprehensive genomic profiling using liquid biopsy can rapidly identify potential candidates for targeted therapy in cervical cancer patients, regardless of histopathology. Clinical studies of precision medicines in Asia are encouraged for such patients.

2 months ago

BRCA Biomarker • Circulating tumor DNA

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • NOTCH1 (Notch 1) • CDK12 (Cyclin dependent kinase 12)

BRCA2 mutation • BRCA1 mutation • HER-2 amplification • PIK3CA mutation • HRD • ATM mutation • CDK12 mutation • HRD + BRCA1 mutation • ATM mutation + CDK12 mutation

Guardant360® CDx

3ms

ORCHID: Study of Olaparib in Metastatic Renal Cell Carcinoma Patients With DNA Repair Gene Mutations (clinicaltrials.gov)

P2, N=20, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Mar 2025

3 months ago

Trial completion date • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BAP1 (BRCA1 Associated Protein 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L)

BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation • RAD51 mutation • CHEK1 expression

Lynparza (olaparib)

3ms

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer. (PubMed, Eur Urol Oncol)

Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms.

3 months ago

Journal

BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • CDK12 (Cyclin dependent kinase 12)

MSI-H/dMMR

3ms

Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial. (PubMed, Ther Adv Urol)

Larger experience is needed in mCRPC with BRCA alterations. NCT03652493, EudraCT ID number 2017-004764-35.

3 months ago

P2 data • Journal • BRCA Biomarker • PARP Biomarker • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)

BRCA2 mutation

carboplatin

3ms

Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes. (PubMed, Ann Oncol)

Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

3 months ago

Journal • BRCA Biomarker • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • HDAC2 (Histone deacetylase 2)

BRCA2 mutation • BRCA1 mutation

3ms

Abemaciclib With or Without Atezolizumab for mCRPC (clinicaltrials.gov)

P2, N=75, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

3 months ago

Enrollment closed

CDK12 (Cyclin dependent kinase 12)

Tecentriq (atezolizumab) • Verzenio (abemaciclib)

3ms

A Study Evaluating Safety and Efficacy of Niraparib in Patients With Previously Treated Metastatic Esophageal/Gastroesophageal Junction/Proximal Gastric Adenocarcinoma (clinicaltrials.gov)

P2, N=43, Active, not recruiting, Shadia Jalal, MD | Trial completion date: Nov 2024 --> Jul 2024 | Trial primary completion date: Nov 2023 --> Feb 2023

3 months ago

Trial completion date • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ARID1A (AT-rich interaction domain 1A) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)

BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • RAD54L mutation • NBN mutation

Zejula (niraparib)

3ms

A Study of Olaparib and Durvalumab in Prostate Cancer (clinicaltrials.gov)

P2, N=5, Terminated, Memorial Sloan Kettering Cancer Center | Completed --> Terminated; Due to low accrual

3 months ago

Trial termination • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1)

BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • BARD1 mutation • FANCA deletion

Lynparza (olaparib) • Imfinzi (durvalumab)

3ms

Pembrolizumab, Olaparib, and Temozolomide for People With Glioma (clinicaltrials.gov)

P2, N=57, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

3 months ago

Trial completion date • Trial primary completion date

EGFR (Epidermal growth factor receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • FGFR (Fibroblast Growth Factor Receptor) • CDK12 (Cyclin dependent kinase 12) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)

CDKN2A deletion • BRIP1 mutation • RAD51C mutation • RAD51B mutation • BARD1 mutation • IDH wild-type

Keytruda (pembrolizumab) • Lynparza (olaparib) • temozolomide

3ms

A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis. (PubMed, Prostate Cancer Prostatic Dis)

Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

3 months ago

Journal • Real-world evidence • Tumor mutational burden • Microsatellite instability • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Real-world • Metastases

TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • PTCH1 (Patched 1) • CDK12 (Cyclin dependent kinase 12) • ATRX (ATRX Chromatin Remodeler)

TMB-H • MSI-H/dMMR • ATRX mutation • PTCH1 mutation

Keytruda (pembrolizumab)

3ms

ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features. (PubMed, J Pathol Clin Res)

ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.

3 months ago

Journal

HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12) • CDH1 (Cadherin 1) • SOX10 (SRY-Box 10)

HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 negative • HR negative • CDK12 mutation • CDH1 mutation • CDK12 amplification

3ms

Circulating tumor DNA and tissue complementarily detect genomic alterations in metastatic hormone-sensitive prostate cancer. (PubMed, iScience)

Integrating tissue and ctDNA analysis identified specific gene alterations (BRCA1, BRCA2, CDK12, TP53, PTEN, or RB1) associated with a shorter time to the progression to castration-resistant prostate cancer (CRPC), with an escalated CRPC risk correlated with cumulative GAs. This multicenter, real-world investigation underscores the complementary role of ctDNA and tissue in detecting clinically pertinent GAs, highlighting their potential integration into clinical practice for advanced prostate cancer management.

3 months ago

Journal • BRCA Biomarker • Circulating tumor DNA • Metastases

TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • CDK12 (Cyclin dependent kinase 12)

BRCA1 mutation

4ms

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets. (PubMed, Int J Mol Sci)

Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets-ATR, CHK1, PARP and their inhibitors.

4 months ago

Review • Journal • PARP Biomarker

RB1 (RB Transcriptional Corepressor 1) • CCNE1 (Cyclin E1) • CDK4 (Cyclin-dependent kinase 4) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • CDK2 (Cyclin-dependent kinase 2) • PKMYT1 (Protein Kinase Membrane Associated Tyrosine/Threonine 1)

TP53 mutation • ATM mutation • CCNE1 amplification • RB1 mutation • TP53 amplification

4ms

Durvalumab and Olaparib for the Treatment of Prostate Cancer in Men Predicted to Have a High Neoantigen Load (clinicaltrials.gov)

P2, N=6, Active, not recruiting, University of Washington | Recruiting --> Active, not recruiting | N=30 --> 6 | Trial completion date: Apr 2026 --> Jun 2025 | Trial primary completion date: Apr 2025 --> Jun 2024

4 months ago

Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date

BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • CD4 (CD4 Molecule) • RAD51D (RAD51 paralog D) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • ABRAXAS1 (Abraxas 1 BRCA1 A Complex Subunit 2) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)

MSI-H/dMMR • HRD

Lynparza (olaparib) • Imfinzi (durvalumab)

4ms

GREAT: A Unique Cohort Of 1500 Advanced Ovarian Cancer (AOC) Patients Treated In Real Life With Prospective Biomarkers Including Tumor BRCA And HRD, And Tumor Collection, A GINECO Study. (ESGO 2024)

GREAT cohort: Main clinical and tumor biological patient characteristicsConclusion Characteristics and treatment of the 1507 pts included in the real-life GREAT prospective study are representative of the standard AOC population. The clinically and biologically annotated GREAT cohort with collection of tumor samples offers a unique opportunity for evaluating new tumor targets for future drug development.

4 months ago

Clinical • BRCA Biomarker • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))

HRD • BRCA mutation

Myriad myChoice® CDx

4ms

Fertility-Sparing Surgery and Adjuvant Chemotherapy with Trastuzumab Result in Complete Remission in a Young Woman with Rare Primary Mucinous Ovarian Cancer due to ERBB2 Co-amplification with CDK12 and Chromosome 11q13.3 Amplicon: A Case Report and Literature Review. (PubMed, Reprod Sci)

Treatment with fertility-sparing surgery and adjuvant chemotherapy with trastuzumab results in complete remission. This novel strategy utilizing precise diagnostics and characterization of the histo-type of rare tumors allowed personalized targeting with optimum drug response for women who yearn fertility preservation and remission from the disease, especially when there is very limited clinical experience on management of such rare ovarian tumors.

4 months ago

Review • Journal • Surgery

HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12)

HER-2 amplification • CDK12 amplification

Herceptin (trastuzumab)

4ms

CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3. (PubMed, Int J Oncol)

Finally, animal experiments were performed for in vivo validation. It was concluded that CDK12 promoted PCa and its angiogenesis by inhibiting IGFBP3.

4 months ago

Journal • Metastases

CDK12 (Cyclin dependent kinase 12) • IGFBP3 (Insulin-like growth factor binding protein 3)

VEGFA expression

4ms

NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness. (PubMed, Oncogene)

Additionally, the chemical inhibition of CDK12 (a downstream transcription CDK of PAF1C) suppressed colon cancer stemness. These results suggest that NELF and PAF1C are the core transcriptional machineries that control expression of colon cancer stemness-inducing genes and may be therapeutic targets for colon cancer.

4 months ago

Journal

CDK12 (Cyclin dependent kinase 12) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • CDK9 (Cyclin Dependent Kinase 9) • CDC73 (Cell Division Cycle 73)

APC mutation

5ms

Pembrolizumab, Olaparib, and Temozolomide for People With Glioma (clinicaltrials.gov)

P2, N=57, Recruiting, Memorial Sloan Kettering Cancer Center

5 months ago

Trial completion date • Trial primary completion date

CDKN2A deletion • BRIP1 mutation • RAD51C mutation • RAD51B mutation • BARD1 mutation • IDH wild-type

Keytruda (pembrolizumab) • Lynparza (olaparib) • temozolomide

5ms

Trans-Regulation of Alternative PD-L1 mRNA Processing by CDK12 in Non-Small-Cell Lung Cancer Cells. (PubMed, Cells)

The fact that CDK12 regulates PD-L1 transcript variant formation in NSCLC cells is consistent with CDK12's role in promoting transcriptional elongation over intron-located poly-A sites. This study lays the groundwork for clinical investigations to delineate the implications of the CDK12-mediated balancing of sPD-L1 relative to mPD-L1 for immunotherapeutic responses in NSCLC.

5 months ago

Journal • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • CDK12 (Cyclin dependent kinase 12)

PD-L1 expression • CDK12 mutation

5ms

DIDO: Niraparib and Dostarlimab in HRD Solid Tumors (clinicaltrials.gov)

P2, N=30, Recruiting, West Cancer Center | Not yet recruiting --> Recruiting

5 months ago

Enrollment open • Combination therapy • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha) • FANCI (FA Complementation Group I)

BRCA1 mutation • HRD • ATM mutation • PALB2 mutation • CHEK2 mutation • BRIP1 mutation • HRD + BRCA1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • RAD54L mutation • FANCI mutation • RAD51 mutation

Zejula (niraparib) • Jemperli (dostarlimab-gxly)

5ms

Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes (clinicaltrials.gov)

P1, N=30, Suspended, National Cancer Institute (NCI) | Initiation date: Oct 2023 --> Jul 2023

5 months ago

Trial initiation date

5ms

The survival outcomes for men with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination deficiencies (HRD) treated with radium-223: Princess Margaret Cancer Centre (PMCC) experience. (ASCO-GU 2024)

A total of 29 (72.5%) patients received 233 Ra following abiraterone or enzalutamide treatment while 10 (25%) received 233 Ra post docetaxel. While the number of patients included in our review was small, our analysis suggested that patients with HRD may have a slight improvement in OS after 223Ra treatment. Validation in a prospective dataset is required, and whether HRD status has implications for other radiopharmaceuticals such as lutetium-177 remains to be seen.

5 months ago

BRCA Biomarker • Metastases

BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2)

HRD • CDK12 mutation • CHEK2 mutation

docetaxel • Xtandi (enzalutamide capsule) • abiraterone acetate • Xofigo (radium Ra-223 dichloride)

5ms

Phase II trial of pembrolizumab for patients suffering from metastatic castration resistant prostate cancer (mCRPC) with DNA repair defects, high tumour mutation burden, and/or high CD3 counts (PERSEUS1). (ASCO-GU 2024)

Pembrolizumab showed prolonged antitumour activity against a subset of molecularly selected mCRPC. Although the analysis met the pre-specified threshold of composite response criteria, due to slow accrual and modest clinical relevance in most responders, it was decided not to continue to stage 2 of the trial. Clinical trial information: NCT03506997.

5 months ago

Clinical • P2 data • Tumor mutational burden • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Metastases

TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CDK12 (Cyclin dependent kinase 12)

TMB-H • MSI-H/dMMR

Keytruda (pembrolizumab)

5ms

Genomic mutations and homologous recombination deficiency (HRD) score in Japanese patients with metastatic hormone-sensitive prostate cancer (mHSPC): The impact of intraductal carcinoma of the prostate (IDC-P). (ASCO-GU 2024)

Among Japanese mHSPC patients, IDC-P demonstrates significant associations with an elevated incidence of genetic alterations and increased HRD score, emphasizing its potential clinical significance.

5 months ago

Clinical • BRCA Biomarker • Metastases

TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • FOXA1 (Forkhead Box A1)

TP53 mutation • HRD • PTEN mutation • CDK12 mutation • BRCA mutation • PTEN mutation + TP53 mutation • High HRD score

Myriad myChoice® CDx Plus