paywalled: Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery: Variability of PARP Activity

Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery: Variability of PARP Activity

Abstract

Purpose: The aim of this study was to evaluate the feasibility of phase 0 trials in the setting of a routine surgical procedure. Logistic considerations, tissue sampling and tissue handling, and variability of a biomarker during surgery, in here PARP, were evaluated. 

Experimental Design: Patients with highly suspicious or proven diagnosis of advanced ovarian cancer, planned for debulking surgery were asked to allow sequential tumor biopsies during surgery. Biopsies were frozen immediately and PARP activity was measured subsequently.

Conclusions: Conducting phase 0 trials during surgery seems to be feasible in terms of logistic considerations. In preparation of a phase 0 trial during surgery, a feasibility study like this should be conducted to rule out major interactions of the surgical intervention with respect to the targeted biomarker.

open access: Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations (technical)

Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations - UKPMC Article - UK PubMed Central

Abstract

Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.

Key words: homologous recombination, PARP inhibitor, BRCA1, BRCA2, PTEN, PALB2, EMSY, double strand break repair

abstract: Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

 Blogger's Note: see recent post for a null finding XRCC/Lynch Syndrome

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.:

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

Am J Hum Genet. 2012 Mar 28;


Abstract

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p<0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

science daily: New breast cancer susceptibility gene (brca)

New breast cancer susceptibility gene

"....XRCC2 may also provide a new target for chemotherapy. "A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It's reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors," said Tavtigian......."

Medical News:Data Confirm PARP Inhibitor (Olaparib) Slows Ovarian Ca - in Meeting Coverage, SGO from MedPage Today

Medical News:Data Confirm PARP Inhibitor Slows Ovarian Ca - in Meeting Coverage, SGO from MedPage Today

Action Points

Note that this randomized, placebo controlled study demonstrates that olaparib, an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor, significantly improved progression-free survival but not overall survival, in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer.

abstract: Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery - Variability of Poly (ADP-Ribose) Polymerase Activity.

Wiki:  Poly ADP ribose polymerase: Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

                   ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery - Variability of Poly (ADP-Ribose) Polymerase Activity.

Abstract

Purpose: 

The aim of this study was to evaluate the feasibility of phase 0 trials in the setting of a routine surgical procedure. Logistic considerations, tissue sampling and handling, and variability of a biomarker during surgery, in here activity of poly(ADP-ribose) polymerase, were evaluated. 

Experimental design: 

Patients with highly suspicious or proven diagnosis of advanced ovarian cancer, planned for debulking surgery were asked to allow sequential tumor biopsies during surgery. Biopsies were frozen immediately and poly (ADP-ribose) polymerase activity was measured subsequently. 

Results: 

Baseline biopsies were obtained from eight patients after a median time of 88 minutes (minimum of 50 to maximum of 123 minutes). Second and third biopsies were obtained after a median of 60 (32-96) and 101 (79-130) minutes, respectively. Mean tumor load was 44% (5%-100%), with a cellular viability of 98% (85%-100%). Median baseline PARP activity was 1035 pg/ml (range: 429-2663 pg/ml). The observed inter-patient variability at baseline was large: standard deviation was 769 before and 0.59 after natural log transformation. 

Conclusions: 

Conducting phase 0 trials during surgery seems to be feasible in terms of logistic considerations. In preparation of a phase 0 trial during surgery, a feasibility study like this should be conducted to rule out major interactions of the surgical intervention with respect to the targeted biomarker.

MBCC: PARP Inhibitors for Breast Cancer—Which Subpopulation to Target? - Cancer Network (BRCA, triple-negative breast...)

MBCC: PARP Inhibitors for Breast Cancer—Which Subpopulation to Target? - Cancer Network

"Speaking at the 29th Annual Miami Breast Cancer Conference, Jorge S. Reis-Filho, PhD, MD, professor of medical pathology at the Institute of Cancer Research in London, England, described the rationale of applying poly (ADP-ribose) polymerase inhibitors (PARP) to breast cancer patients.

Tumors that have a loss of function in DNA-repair genes such as BRCA1 and BRCA2, and homologous recombination, as Dr. Joyce O'Shaughnessy described during her session on emerging triple-negative breast cancer therapies, may be particularly sensitive to PARP inhibitors.

Reis-Filho highlighted that sequencing tumors may not be enough to characterize whether tumors have intact DNA-repair pathways—tumors also have epigenetic changes that regulate homologous recombination......"

press release: Mapping of protein inhibitors facilitates development of tailor-made anticancer agents

Press release (reducing side effects of parp inhibitors)
 Karolinska Institutet

updated - link to full free paper: Review: Therapeutic strategies in epithelial ovarian cancer (references clear cell ovarian)

 Blogger's Note: numerous references to clear cell ovarian cancer as per Japanese historical ovarian cancer research



direct link to pdf file 

 "In summary, it appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas are, in fact, secondary.

Previous data support the view that serous tumors develop from the fimbria, the most distal part of the fallopian tube, endometrioid and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact to the peritoneum.

Although the data suggesting that epithelial ovarian carcinoma arises in extra-ovarian sites and involves the ovaries secondarily are compelling, low- and high-grade serous carcinomas involve the ovaries and other pelvic and abdominal organs, such as the omentum and mesentery, much more extensively than the fallopian tubes. Similarly, although endometrioid carcinomas develop from endometriosis, which frequently involves multiple sites in the pelvis, these tumors are usually confined to the ovaries.

It is likely that the predisposition for
growth in the ovary is multifactorial but the precise reasons for this are unknown."

Hereditary ovarian cancer: Beyond the usual suspects - abstract (Fanconi anemia–BRCA,PARP, RAD51C, RAD51D,BRIP1

Blogger's Note: see post Myriad Genetics  rights/RAD51C

.....With at least 16 genes implicated in hereditary ovarian cancer to date, comprehensive testing for ovarian cancer risk will require assessment of many genes........ In addition, identifying inherited mutations in a variety of FA–BRCA pathway genes may aid in identifying individuals who will selectively benefit from PARP inhibitors."

---

Highlights

► Newly identified hereditary ovarian cancer genes include RAD51C, RAD51D, and BRIP1.
► Many genes in the Fanconi anemia–BRCA pathway may increase risk of ovarian cancer.
► New genomic technologies make comprehensive genetic assessment feasible.

phase 11 - Cancer Research UK launches 'outpatients' (oral)trial of breast and ovarian cancer drug (BRCA/serous cell type - AG-014699 known as Rucaparib or CO-338 - PARP inhibitor)

" Cancer Research UK’s Drug Development Office has re-launched a trial of a promising drug to treat inherited breast and ovarian cancer – but this time taken as a tablet by outpatients."
 
"Women with advanced breast or ovarian cancer with faults in the known high-risk BRCA1 or BRCA2 genes will receive the drug called AG-014699 (Rucaparib) – which belongs to a promising class of drugs called PARP inhibitors. The trial is also open to women with advanced serous ovarian cancer but unknown BRCA status."

"Notes to editors

The drug AG-014699 (also called Rucaparib or CO-338) was recently licenced to Clovis Oncology from Pfizer."

Clinical Oncology News - Mixed News on PARP Inhibitors Presented at ASCO Meeting

Poly(ADP-Ribose) Polymerase Inhibition Synergizes with 5-Fluorodeoxyuridine but not 5-Fluorouracil in Ovarian Cancer Cells-abstract

"5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism." "These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors."

Search Results: parp - 2011 ASCO Abstracts

Search: parp

Found 141 documents

press release: Pfizer Licenses PARP Inhibitor To Clovis Oncology (PF-01367338)

"...PF-01367338 would be developed by Clovis as both a monotherapy and in combination with chemotherapeutic agents for the potential treatment of selected cancer patients.
PF-01367338 is currently in a Phase 1 clinical trial examining the maximum tolerated dose of oral PF-01367338 that can be combined with intravenous platinum chemotherapy in the treatment of solid tumors.
Supplementing this trial are two ongoing trials, currently using the IV formulation, a Phase 1/2 study in germline BRCA-mutant (gBRCA) breast and ovarian cancer and a Phase 2 study in the adjuvant treatment of triple negative breast cancer. Clovis intends to replace the IV formulation with the oral formulation in these studies.
Clovis was founded by former executives of Pharmion Corp., which was acquired by Celgene Corporation in 2008. The company is headquartered in Boulder, Colorado, and has additional offices in San Francisco and London."

May 20th Medscape - PARP Inhibitor Improves Outcomes in Ovarian Cancer - olaparib

worth reading - Medical News: SGO: PARP Inhibitor Active in Ovarian Cancer - in Meeting Coverage, SGO from MedPage Today

......"Antitumor activity was observed in heavily pretreated BRCA1 and BRCA2 mutation carriers, and preliminary antitumor activity was seen in patients with sporadic cancers," said Robert Wenham, MD, of the H. Lee Moffitt Cancer Center in Tampa, Fla...........During the initial dose-escalation phase, the patient population was enriched with BRCA1/2 mutation carriers. In the dose-expansion phase of the trial, investigators enrolled patients with sporadic platinum-resistant high-grade serous ovarian cancer......cont'd

MSKCC (Memorial Sloan Kettering) Winter 2011 newsletter Molecular Medicine for Ovarian and Endometrial Cancer - Douglas A Levine

Note: includes reference to PARP inhibitors

Download Article - Update in Gynecologic Oncology, Winter 2011

full free access: Poly(ADP-Ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic - A Cancer Journal for Clinicians - Wiley Online Library

see also:   
Table 1. DNA Repair Pathways
(Lynch Syndrome, BRCA 1/2, FANC, ATM, MYH ;  
Table 2. PARP Inhibitor Clinical Trials; Other Potential Synthetic Lethal Strategies for PARP Inhibitors.....

Conclusions: 
"The synthetic lethal targeting of DNA repair pathways, as exemplified by PARP inhibitors, in cancers bearing HR DNA repair defects is showing considerable potential for delivering selective tumor cell kill while sparing normal cells, and offers a scientifically rational and potentially broad clinical application in oncology.64 Several challenges related to the development of these inhibitors remain, including the identification of robust predictive biomarkers of HR deficiency in cancers. The dissection of the underlying mechanisms of PARP inhibitor resistance and establishment of optimal drug combinations and strategies for chemoprophylaxis with these therapies remain high priorities. It is important to be aware that different PARP inhibitors may have varying potencies on individual members of the PARP superfamily and also affect other targets, resulting in distinct toxicity and efficacy profiles. In the future, it is envisioned that this tumor-specific synthetic lethal strategy with PARP inhibitors may potentially be utilized against cancers with similar molecular defects but diverse anatomical origins.118 Such a paradigm shift in drug discovery may crucially bring us closer to our ultimate goal of personalized medicine."

PARP (1 and 2) inhibitor, MK-4827, shows anti-tumor activity in first trial in humans (mutation/non mutation carriers)

"He gave a possible explanation as to why patients with cancers that were not caused by BRCA1/2 mutations also responded to the PARP inhibition. "BRCA is a tumour suppressor gene that assists in repairing double stranded DNA breaks. In BRCA-mutation related cancers, loss of both copies of the gene results in a non-functional protein and thus BRCA deficiency. Because BRCA works with other proteins, BRCA-pathway related deficiency can be seen in the absence of two mutated copies of the BRCA genes. This may explain why responses have been reported for this class of drugs in non-BRCA mutant cancers."