paywalled: Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology

Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology

Current Opinion in Oncology:

May 2012 - Volume 24 - Issue 3 - p 316–324

doi: 10.1097/CCO.0b013e32835280c6

INNOVATIVE EARLY CLINICAL TRIALS METHODOLOGY AND NEW THERAPEUTICS IN CANCER: Edited by Ahmad Awada

Targeting the DNA damage response in oncology: past, present and future perspectives

Abstract

Purpose of review: 

The success of poly(ADP-ribose) polymerase inhibition in BRCA1 or BRCA2 deficient tumors as an anticancer strategy provided proof-of-concept for a synthetic lethality approach in oncology. There is therefore now active interest in expanding this approach to include other agents targeting the DNA damage response (DDR). We review lessons learnt from the development of inhibitors against DNA damage response mechanisms and envision the future of DNA repair inhibition in oncology.

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

Future Science - abstract: Targeted cancer therapy: giving histone deacetylase inhibitors

Future Science - Future Medicinal Chemistry - 4(4):505 - Summary

Review

Abstract

Targeted cancer therapy: giving histone deacetylase inhibitors

"Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis – SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). 

However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution."

links to article/commentary/blogger's notes: Intravenous Aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study : The Lancet Oncology

Blogger's Note:  reposted from Jan 20th due to Lancet Editorial and reference - paper is open accdess

• pay specific attention to patient safety/adverse events; 

  • related article on the (beneficial) use of Aflibercept in colorectal cancer patients (Aflibercept Improves Survival In Metastatic Colon Cancer - December 2011)

Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study Aflibercept

 Interpretation

This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit—risk balance should be thoroughly discussed for each patient.

 Commentary: 

VEGF Trap for the treatment of malignant ascites

Gerhild Becker, Hubert E Blum

"In view of the important pathogenetic role of VEGF in ascites formation, the efficacy of VEGF inhibitors have also been assessed in patients with symptomatic malignant ascites. Confirming the results of a recent open-label single-arm phase 2 trial,6 the randomised double-blind placebo-controlled study by Walter Gotlieb and colleagues7 in The Lancet Oncology shows the efficacy of aflibercept in patients with malignant ascites associated with advanced ovarian cancer and can be interpreted as proof of concept. The intervention and the control groups were homogenous, confounding variables controlled, and bias reduced. Therefore, the study has a high internal validity and shows the efficacy of aflibercept. With respect to the clinical implications of the results, symptom relief has to be weighed against discomfort and potentially life-threatening adverse events (three patients had fatal gastrointestinal complications in the aflibercept group vs one in the placebo group), since the treatment is applied to patients in a highly palliative situation. Careful patient selection could reduce the incidence of gastrointestinal perforations. However, before a general recommendation of aflibercept for the treatment of malignant ascites can be made, further studies, including comparative effectiveness research,8 (Blogger's Note: AND patient safety) are needed to compare the effectiveness of the different therapeutic strategies in daily clinical practice."

preview: RAF around the Edges — The Paradox of BRAF Inhibitors — NEJM

RAF around the Edges — The Paradox of BRAF Inhibitors

N Engl J Med 2012; 366:271-273January 19, 2012

This article has no abstract; the first 100 words appear below.

The recent success of BRAF inhibitors represents a great stride forward for melanoma research. When used to treat patients with melanoma who harbor the BRAF V600E mutation, these inhibitors lead to the remission of even advanced lesions. However, resistance to BRAF inhibitors emerges within months. Of added concern is the development of secondary tumors, most commonly cutaneous squamous-cell carcinomas and keratoacanthomas, in response to BRAF inhibition.¹ In this issue of the Journal, Su et al. found that BRAF inhibition leads to increased MAPK (mitogen-activated protein kinase) signaling and secondary tumor development when another oncogene, HRAS, is activated.² This is due . . .

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."

abstract: Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer (inhibitors)

PURPOSE:
Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways.

METHODS:
This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase).

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."

abstract/Cochrane Collaboration review: DNA-repair pathway inhibitors for the treatment of ovarian cancer (PARPs...AZD2281)

Plain language summary

Are DNA repair inhibitors as effective and harmless compared to conventional chemotherapy in the treatment of ovarian cancer?
Ovarian cancer is the sixth commonest cancer in women world-wide and remains a leading cause of death, with an annual incidence of 6.6 cases per 100,000 women and an annual mortality rate of 4.0 deaths per 100,000 women. Most ovarian cancers (90%) are epithelial ovarian cancer and arise from the surface of the ovary. Epithelial ovarian cancer typically occurs in post-menopausal women, with a peak incidence around the age of 60, although it does occur in younger women, often associated with genetic predispositions. The onset of this disease is insidious and 75% of women present with advanced stage disease (stage III or IV) when the 5 year survival is around 30%. Treatment consists of debulking surgery and platinum-based chemotherapy, with or without taxanes. Although initial response to chemotherapy is good, most women will relapse, requiring further chemotherapy treatment and develop cancer that is resistant to chemotherapy.

Conventinal chemotherapy acts on all rapidly dividing cells by damaging DNA. Cancer cells divide very rapidly, which is why chemotherapy works better on cancer cells than normal cells. However, there is no inherent selectivity for normal calls and so rapidly dividing cells, such as gut lining, hair follicles and bone marrow, are also affected, leading to diarrhoea, mouth ulcers, hair loss, anaemia and susceptibility to infections.

All cells are equipped with a number of systems or pathways that repair DNA damage. If cells are unable to repair their DNA, the cell undergoes programmed cell death (apoptosis) in order to prevent an abnormal cell from dividing. Because being able to repair DNA is vital to cell survival, normal cells have more than one DNA-repair pathway, so that if one is lost cells can still repair themselves. Cancer cells often develop defects in these pathways, due to mutations, which may promote development of cancer (e.g. BRCA mutations). However, these same mutations mean that these cancer cells are more susceptible to DNA damage, such as that caused by chemotherapy, than normal cells. Novel therapeutical agents have been developed to inhibit DNA-repair pathways, which makes cells that already have faults in another DNA repair pathway due to a mutation, exquisitely sensitive to DNA damaging chemotherapy agents. The most common target for this type of novel anti-cancer agent are the DNA-repair enzymes called poly (ADP-ribose) polymerases (PARPs). PARPs are a family of related enzymes, which are involved in regulating various cellular processes, including DNA repair, cell death, and inflammation. PARP inhibitors therefore have a potentially wide range of applications.

Our objective was to compare effectiveness and side effects of PARP inhibitors compared to conventional chemotherapy in women with ovarian cancer. The identification of a safe dose of AZD2281 (a PARP inhibitor) has been found by small non randomised trials, with encouraging results. For ovarian cancer, there are currently two ongoing RCTs, but outcome data are not yet available. Results of these trials are awaited to determine if DNA repair inhibitors have a role in addition to conventional chemotherapy in the treatment of ovarian cancer.

Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression; Expert Opinion