scholarly journals Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Francesco Sabbatino ◽  
Luigi Liguori ◽  
Umberto Malapelle ◽  
Francesca Schiavi ◽  
Vincenzo Tortora ◽  
...  
Keyword(s):  
Dna Repair ◽  
Intrahepatic Cholangiocarcinoma ◽  
Therapeutic Option ◽  
Clinical Care ◽  
Parp Inhibitor ◽  
Stage Iv ◽  
Predictive Biomarkers ◽  
Poor Response ◽  
Precision Oncology ◽  
Repair Pathway

IntroductionIntrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.Case presentationWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.ConclusionThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

High dose testosterone in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5095-TPS5095 ◽  
Author(s):  
Julia Chen ◽  
Anthony M. Joshua ◽  
Samuel R. Denmeade ◽  
Emmanuel S. Antonarakis ◽  
Megan Crumbaker
Keyword(s):  
Dna Repair ◽  
Clinical Data ◽  
Response Rate ◽  
De Novo ◽  
Tumor Regression ◽  
Parp Inhibitor ◽  
Significant Risk ◽  
Predictive Biomarkers ◽  
Serum Testosterone ◽  
High Dose

TPS5095 Background: mCRPC progresses via adaptive mechanisms that allow ongoing androgen receptor (AR) signalling despite castrate levels of androgens. Bipolar androgen therapy (BAT), cycling between supraphysiologic and subphysiologic serum testosterone levels, aims to exploit these adaptations to induce tumor regression. Extensive clinical data demonstrate the safety and efficacy of BAT in men with asymptomatic mCRPC. However, de novo resistance is still common and predictive biomarkers to refine patient selection are lacking. Pre-clinical data suggest that the induction of double-stranded DNA (dsDNA) breaks by BAT may be crucial to its mechanism of action. DNA repair defects, such as HRD, are particularly relevant in CRPC patients. We hypothesize that CRPC patients with DNA repair deficits such as HRD, may be particularly responsive to BAT. Methods: This is a phase II prospective single arm interventional trial (NCT03522064). Up to 30 patients will be recruited based on a Simon two-stage design with a power of 90% to detect an increase in response rate from 20% to 40%. Key inclusion criteria include i) asymptomatic or minimally symptomatic mCRPC, ii) rising PSA despite a castrate serum testosterone and iii) HRD on germline, tumor and/or circulating tumor DNA (ctDNA) analysis. Key exclusion criteria include i) ADT < 1 year, ii) disease extent/sites that would cause significant risk if tumor flare occurs (e.g.: brain) and iii) significant cardiac disease. Previous PARP inhibitor therapy will be permitted in a subset. Participants will receive IM testosterone enanthate 500mg q4w in combination with ongoing LHRH antagonist/agonist or orchidectomy. The primary endpoint is PSA response rate defined as PSA reduction ≥50% from baseline. Secondary endpoints include time to PSA progression, quality of life, radiologic response and safety and tolerability. Exploratory endpoints include changes in ctDNA and tumoral DNA alterations from baseline to progression. Accrual is ongoing. Clinical trial information: NCT03522064.

scholarly journals PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
Author(s):  
Boussios ◽  
Karathanasi ◽  
Cooke ◽  
Neille ◽  
Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Repair Pathway ◽  
Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

scholarly journals An Analysis of Patients with DNA Repair Pathway Mutations Treated with a PARP Inhibitor

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Erkut Borazanci ◽  
Ronald Korn ◽  
Winnie S. Liang ◽  
Carol Guarnieri ◽  
Susan Haag ◽  
...  
Keyword(s):  
Dna Repair ◽  
Parp Inhibitor ◽  
Repair Pathway

DNA-repair pathway expression changes and their correlation with PDAC sensitivity to PARP- inhibitor and chemotherapy combination

Pancreatology ◽  
2020 ◽  
Vol 20 ◽  
pp. S139-S140
Author(s):  
B. Mohelnikova-Duchonova ◽  
O. Strouhal ◽  
T. Zemanek ◽  
K. Kolarova ◽  
D. Flasarova ◽  
...  
Keyword(s):  
Dna Repair ◽  
Parp Inhibitor ◽  
Repair Pathway ◽  
Pathway Expression

scholarly journals Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2647
Author(s):  
Suzanne Bakewell ◽  
Isabel Conde ◽  
Yassi Fallah ◽  
Mathew McCoy ◽  
Lu Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Parp Inhibitor ◽  
Maximum Tolerated Dose ◽  
Repair Pathway

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 μM, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER−) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER− breast cancer.

Avenues to Precision Oncology

2020 ◽  
pp. 36-45
Author(s):  
Alexander Meisel
Keyword(s):  
Precision Medicine ◽  
Trial Design ◽  
Ad Hoc ◽  
Molecular Targets ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Precision Oncology ◽  
Companion Diagnostics ◽  
Bona Fide ◽  
The One

Until recently, the clinical management of cancer heavily relied on anatomical and histopathological criteria, with ad hoc guidelines directing the therapeutic choices in specific indications. In the last years, the development and therapeutic implementation of novel anticancer therapies significantly improved the clinical outcome of cancer patients. Nonetheless, such cutting-edge approaches revealed the limitation of the one-size-fits-all paradigm. The newly discovered molecular targets can be exploited either as bona fide targets for subsequent drug development, or as tools to precision medicine, in the form of prognostic and/or predictive biomarkers. This article provides an overview of some of the most recent advances in precision medicine in oncology, with a focus on novel tissue-agnostic anticancer therapies. The definition and implementation of biomarkers and companion diagnostics in clinical trials and clinical practice are also discussed, as well as the changing landscape in clinical trial design.

Efficacy and safety of oral dapsone in acne vulgaris – experience of a tertiary care teaching hospital in central Lahore

2020 ◽  
Vol 14 (2) ◽  
pp. 87-90
Author(s):  
Sadaf Amin Chaudhry ◽  
Nadia Ali Zafar ◽  
Rabia Hayat ◽  
Ayesha Noreen ◽  
Gulnaz Ali ◽  
...  
Keyword(s):  
Side Effects ◽  
Therapeutic Option ◽  
Acne Vulgaris ◽  
Treatment Options ◽  
Tertiary Care ◽  
Poor Response ◽  
Global Assessment Scale ◽  
Severe Acne ◽  
Hematologic Profile

Background: Acne is the eighth most prevalent disease affecting 9.4% of the population worldwide and its prevalence in our country is estimated to be around 5%. Severe inflammatory acne is most likely to leave scars and in order to prevent facial disfigurement due to acne scarring, early treatment is desirable. Various treatment options have been formulated for acne, and are tailored according to the severity of the disease. Numerous clinical trials have been conducted till now, to determine the usefulness and side effect profile of such therapies, making acne treatment a highly studied area in dermatology. Objective of this study is to highlight the fact that oral Dapsone could be used as a cheaper alternate to isotretinoin in recalcitrant severe acne, especially in females where retinoids are sometimes contraindicated. Patients and methods: 51 patients, suffering from severe nodulocystic acne, fulfilling the criteria, were enrolled from the Department of Dermatology, Sir Ganga Ram Hospital, Lahore. All the study patients were given oral Dapsone 50mg for initial two weeks and then 100mg daily for the next 10 weeks along with oral cimetidine and topical clindamycin application twice daily. Investigator Global Assessment Scale (IGAS) was employed to measure effectiveness. The treatment was considered ʽeffectiveʹ if the patient achieves 2 or more than 2-grade improvement or almost clear or clear skin at the end of 12 weeks according to IGAS scale. The lesion counts were also done before the start of therapy (day 1) and at every two weeks follow up for 12 weeks. The change in lesion count observed between the baseline number and that seen at follow up visits was also used to evaluate the effectiveness of oral Dapsone. Safety was analyzed by fortnightly visits of the patients to look for any undesirable side effects and monitoring of the hematologic profile of the patients. Final follow up was done at the end of 16 weeks. Results: The study was conducted on 51 patients, with a ratio of 1:3 for males and females and a mean age of 25.2 years (SD ±5.81). At 12th week, patients had significant reduction in their acne lesions; with 7 patients (13.7%) showing completely clear skin, 17 patients (33.3%) had almost clear skin, 5 patients (9.8%) had 3-grade improvement. Twelve patients (23.5%) had 2-grade improvement from baseline score and only 2 patients (3.9%) had 1-grade improvement from baseline. Based on percentage reduction of lesions, excellent response was seen in 32 patients (62.7%), good response in 9 patients (17.6%), moderate response in 2 patients (3.9%), while no patient showed poor response. Dapsone was discontinued in 8 patients due to derangement of hematologic profile. Conclusion: Oral Dapsone, when given carefully, is a very effective therapeutic option in severe recalcitrant acne, with limited side effects.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

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