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PARP
PARP PARP(7)
PARP is a nuclear family of proteins involved in DNA repair, apoptosis, and expression of inflammatory genes.(2) The PARP family comprises 17 members with different structures and functions.(1) PARP has four domains: a DNA-binding domain, a caspase-cleaved domain, an auto-modification domain, and a catalytic domain.(1)
PARP activation is an immediate cellular response to metabolic, chemical, or radiation-induced DNA SSB damage. In the presence of damaged DNA, the DNA-binding domain binds the DNA and induces a conformational shift.(1) Once PARP detects a SSB, it binds to the DNA, and, after a structural change, begins the synthesis of a poly (ADP-ribose) chain (PAR) as a signal for the other DNA-repairing enzymes, DNA polymerase β (polβ), and scaffolding proteins. The catalytic domain is responsible for PAR polymerization. PAR polymer can reach lengths of up to 200 nucleotides before inducing apoptotic processes. The auto-modification domain releases the protein from the DNA after catalysis and plays a role in cleavage-induced inactivation.(1) Activated PARP can deplete the ATP of a cell in an attempt to repair the damaged DNA. ATP depletion in a cell leads to lysis and necrosis.(3) PARP-mediated post-translational modification of proteins can affect the amount of DNA methylation at CpG dinucleotides. PARP has also been proposed to affect the amount of DNA methylation.(1) PARP is inactivated by caspase cleavage.(1, 4)
PARP-2 has been shown to oligomerize with PARP-1. The oligomerization has also been shown to stimulate PARP catalytic activity. PARP-1 is also known for its role in transcription through remodeling of chromatin by PARylating histones and relaxing chromatin structure. PARP-mediated DNA repair capability may contribute to mammalian longevity. This suggests that un-repaired DNA damage is an underlying cause of aging and that DNA repair capability contributes to longevity.(1)
While in vitro cleavage by caspase occurs throughout the caspase family, caspase-3 and caspase-7 may be responsible for in vivo cleavage. The DNA-binding region is capable of doing so independent of the rest of the protein, cleaved or not. It is unable, however, to dissociate without the auto-modification domain. In this way, the DNA-binding domain will attach to a damaged site and be unable to affect repair, as it no longer has the catalytic domain. The DNA-binding domain prevents other, non-cleaved PARP from accessing the damaged site and initiating repairs. This model suggests that this sugar plug can also begin the signal for apoptosis. It is interesting to note that NAD+ is required as substrate for generating ADP-ribose monomers. The over-activation of PARP may deplete the stores of cellular NAD+ and induce a progressive ATP depletion, since glucose oxidation is inhibited, and necrotic cell death. In this regard, PARP is inactivated by caspase-3 cleavage during programmed cell death.(1)
The tankyrases are PARPs that comprise ankyrin repeats, oligomerization domain (SAM), and a PARP catalytic domain (PCD). Tankyrases are also known as PARP-5a and PARP-5b. They were named for their interaction with the telomere-associated TRF1 proteins and ankyrin repeats. They may allow the removal of telomerase-inhibiting complexes from chromosome ends to allow for telomere maintenance. It also plays a role in spindle assembly through its interaction with nuclear mitotic apparatus (NuMa), therefore allowing bipolarity. In the absence of TNKs, mitosis arrest is observed in pre-anaphase through Mad2 kinetochore checkpoint. TNKs can also PARsylate Mcl-1L and Mcl-1S and inhibit both their pro- and anti-apoptotic function.(1)

Drugs/Indications
Marketed Drugs/Indications
Generic Code Old Code Brand Company Indication trials
olaparib AZD2281 KU0059436 Lynparza AstraZeneca Mkt: ovarian; P3: BC, gastric, P2: solid,pancreatic, melanoma, CRC; P1: solid, HCC, Ewing's, brain, CNS, HNN, PC trials
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
niraparib MK-4827 TESARO P3: ovarian, BC; P2: lymphoma; P1: Ewing's, solid, GBM trials
rucaparib PF-01367338 AG-014699 Pfizer P3: ovarian, fallopian, peritoneal; P2: BC, pancreatic; P1: solid trials
veliparib ABT-888 Abbvie P3: BC, NSCLC; P2: CRC, lymphoma, melanoma, ovarian, HCC, SCLC, solid; P1/2: PC; P1: leukemia, MDS, pancreatic, rhabdoid, gastric trials
talazoparib BMN 673 Biomarin P3: BC; P2: endometrial, ovarian, solid; P1: AML, MDS, CLL trials
E7016 Eisai P2: melanoma; P1: solid trials
E7449 Eisai P1/2: solid, ovarian, BC, melanoma trials
ABT-767 Abbvie P1: fallopian, peritoneal, solid, BC, ovarian, PC, pancreatic trials
AZD2461 AstraZeneca P1: solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
iniparib SAR240550 BSI-201 Sanofi Discontinued; ineffective; does not actually inhibit PARP; P3: NSCLC, BC, solid; P2: peritoneal, ovarian, brain: P1/2: GBM; P1: solid trials
CEP-9722 Cephalon terminated; P1/2: solid; P1: MCL trials
INO-1001 Roche terminated; P1: melanoma trials
News
References

1. Chipuk JE MT, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell. 2010;37(3):299-310. PMCID: 20159550.

2. Zerfaoui M, Suzuki Y, Naura AS, Hans CP, Nichols C, Boulares AH. Nuclear translocation of p65 NFκB is sufficient for VCAM-1, but not ICAM-1, expression in TNF-stimulated smooth muscle cells: differential requirement for PARP-1 expression and interaction. Cellular signalling. 2008;20(1):186-94.

3. Yu S-W, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, et al. Apoptosis-inducing factor mediates poly (ADP-ribose)(PAR) polymer-induced cell death. Proceedings of the National Academy of Sciences. 2006;103(48):18314-9.

4. Doetsch M, Gluch A, Poznanovi? G, Bode J, Vidakovi M. YY1-binding sites provide central switch functions in the PARP-1 gene expression network. PLoS One. 2012;7(8):e44125.

5. Zeitlin SG. Centromeres: The wild west of the post-genomic age. Epigenetics. 2010;5(1):34-40. PMCID: 20093854.

6. SG Z. Centromeres The wild west of the post-genomic age. Epigenetics. 2010;5(1):34-40.

7. Ratnam K, Low JA. Current development of clinical inhibitors of poly (ADP-ribose) polymerase in oncology. Clinical Cancer Research. 2007;13(5):1383-8.



News
Tuesday, September 20, 2016 6:00 PM|Cancer Research UK|Cancer Research UK News|Labels: PARP

Press release

Cancer Research Technology (CRT) – the development and commercialisation arm of Cancer Research UK – and SV Life Sciences have today announced the launch of Artios Pharma, a new company formed to develop drugs targeting the DNA damage response in cancer.

Artios has licensed its two lead DNA damage response programmes from CRT and has signed a non-exclusive research collaboration agreement through which Artios will work with CRT Discovery Laboratories to progress the lead programmes, and discover and develop additional promising drug targets selected from Cancer Research UK’s portfolio of DNA damage repair research. 

“We are pleased to have worked with SV Life Sciences to bring together the Cancer Research UK academic network, a portfolio of leading DNA damage response opportunities and the CRT Discovery Laboratories’ drug discovery platform to help build a strong development pipeline for Artios."Dr Keith Blundy, CRT’s chief executive officer

DNA damage response therapies target the way cancer cells repair damaged DNA. Faults in DNA repair lead to an increased risk of cancer and drive the growth of tumours. Blocking the repair mechanisms on which cancer cells rely has been shown to selectively kill them.

These DNA damage response targeted therapies have the potential to work alone or in combination with chemotherapy, radiotherapy or immunotherapy drugs.

The company’s lead programme targets the pol-theta molecule and builds on cutting-edge cell biology research from Professor Gillies McKenna’s and Dr Geoff Higgins’ laboratories at the Cancer Research UK/MRC Oxford Institute for Radiation Biology

The pol-theta molecule is thought to control DNA repair processes in certain tumours. Knocking out the target could remove a vital path relied on by the cancer cell, causing it to die. A second highly promising programme against an undisclosed target has also been licensed to Artios.

Artios is actively building a pipeline of promising first-in-class DNA damage response therapies from leading researchers in the field. Cancer Research UK’s extensive research base will provide the foundation for CRT to provide Artios with additional new molecular targets and establish collaborative partnerships with world-class scientists in the DNA damage response field.

Under the terms of the agreements, CRT will receive research funding into its Discovery Laboratories, equity in the company, and be eligible to receive milestone payments and royalties on projects advancing through Artios’ drug pipeline. 

Led by SV Life Sciences, Artios has raised series A financing of £25million ($33.2million) from Merck Ventures, Imperial Innovations, Arix Bioscience PLC, CRT Pioneer Fund (managed by Sixth Element) and AbbVie Ventures.

Dr Keith Blundy, CRT’s chief executive officer, said: “We are pleased to have worked with SV Life Sciences to bring together the Cancer Research UK academic network, a portfolio of leading DNA damage response opportunities and the CRT Discovery Laboratories’ drug discovery platform to help build a strong development pipeline for Artios. This exciting development has enabled us to leverage the expertise of the Artios management team and financing from leading venture companies to help establish a company that has the potential to bring real impact to cancer patients.”

Kate Bingham, managing partner at SV Life Sciences, said: “Artios represents a unique opportunity to build a world-class DNA damage response pipeline through partnerships with leading DNA repair researchers in the UK and worldwide. We are delighted to have worked together with CRT to form this company and are pleased with the strong investor interest in Artios, reflecting the potential of DNA damage response. With the strength of their management team, Artios has the potential to disrupt the DNA damage response space and provide significant new therapies for cancer patients.”

Dr Niall Martin, CEO of Artios Pharma, said: “Targeting the DNA damage response is an exciting and promising field of biology with growing interest following the recent success of PARP inhibitors. DNA damage response drug products have the potential to become established as first-line treatments, either as single agents or for use in combination with many approved therapies. It is an ideal time for Artios to be entering the field as a DNA damage response-focused, independent biotech company. We’re delighted to welcome our world-class investors to the company and to announce our first partnership with Cancer Research Technology.”

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Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: PARP, childhood cancer, sarcoma
The purpose of this study is to define the dose-limiting toxicities and maximum tolerated dose of the poly ADP-ribose polymerase inhibitor niraparib and escalating doses of temozolomide in patients with pre-treated incurable Ewing sarcoma.
Monday, September 12, 2016 7:15 AM|Onclive Articles|Labels: PARP, ovarian cancer, regulatory
The FDA has granted a fast track designation to niraparib, allowing the initiation of a rolling submission of data for potential approval for the PARP inhibitor as a treatment for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.
Monday, September 12, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: PARP, regulatory
Tesaro Inc. (NASDAQ:TSRO) said it began rolling submission of an NDA to FDA for niraparib (MK-4827) to treat recurrent, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer. It expects to complete the submission next quarter. Also on Monday, Tesaro said FDA granted Fast Track designation to the oral PARP inhibitor. In June, niraparib met the primary endpoint of the Phase III NOVA trial, improving progression-free survival vs. placebo in patients with and without germline BRCA mutations (see BioCentury, July 11). The company said it plans to submit an MAA to EMA next quarter for niraparib.Tesaro gained $1.60 to $93.19 on Monday.
Tuesday, September 6, 2016 8:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: PARP, prostate cancer
The loss of CHD1, one of the most frequently mutated genes in prostate tumors, sensitizes human prostate cancer cells to different drugs, including PARP inhibitors.
Tuesday, September 6, 2016 7:00 AM|Anonymous|American Pharmacists Association - Improving medication use. Advancing patient care.|Comments|Labels: PARP, ovarian cancer

A new class of drugs, known as PARP inhibitors, could be a significant step forward in the treatment of ovarian cancer. The drugs are thought to help the body slow the disease's progression by helping to prevent cancer cells from repairing themselves after chemotherapy treatment, thereby shrinking tumors and delaying relapses. The drugs do not work in everyone, and are thought to have the greatest effect in women with mutations of the BRCA genes, who represent about 15% of ovarian-cancer patients.

Monday, September 5, 2016 9:48 AM|Human Biology News -- ScienceDaily|Labels: PARP, prostate cancer
The loss of CHD1, one of the most frequently mutated genes in prostate tumors, sensitizes human prostate cancer cells to different drugs, including PARP inhibitors. This suggests CHD1 as a potential biomarker for targeted prostate cancer therapy, report scientists.
Monday, August 22, 2016 8:35 AM|Pratz, K. W., Rudek, M. A., Gojo, I., Litzow, M. R., McDevitt, M. A., Ji, J., Karnitz, L., Herman, J. G., Kinders, R., Smith, B. D., Gore, S. D., Carraway, H., Showel, M. M., Gladstone, D. E., Levis, M. J., Tsai, H.-L., Rosner, G. L., Chen, A., Kaufmann, S. H., Karp, J.|Clinical Cancer Research Online First Articles|Labels: PARP, CML

Purpose: The poly(ADP-ribose) polymerase (PARP) inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPNs) and chronic myelomonocytic leukemia (CMML). Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on Days 1-8, 1-14 or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on Days 3-7. The maximum tolerated dose was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival (hazard ratio .56 (95% CI .27-.92)). A single 80 mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders. Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias.

Sunday, August 14, 2016 10:05 PM|Serra, V., Cruz, C., Castroviejo, M., Gutierrez, S., Llop, A., Bruna, A., Morancho, B., Caratu, G., Prudkin, L., Vivancos, A., Nuciforo, P., O'Connor, M., Jonkers, J., Caldas, C., Arribas, J., Baselga, J., Rubio, I. T., Saura, C., Diez, O., Balmana, J., Cortes, J.|Clinical Cancer Research recent issues|Labels: BRCA, PARP, breast cancer, ovarian cancer

Background: Women with heterozygous germline mutations in BRCA1 or BRCA2 are predisposed to developing breast or ovarian cancers, since BRCA1/2 mutation results in impaired high-fidelity DNA repair by homologous recombination (HR) and subsequently genetic instability. In non-gBRCA TNBC, HR deficiency occurs at the somatic level, by means of BRCA1 mutation, BRCA1 epigenetic loss or mutation in other HR-associated genes. PARP1/2 inhibitors (PARPi) are active anti-cancer agents in gBRCA with advanced breast or ovarian cancer. However, not all HR-deficient tumors respond to PARP blockade, and eventually all develop acquired resistance. Here, we sought to identify PARPi response biomarkers using PDX derived from both the early disease and the metastatic setting.

Methods: We developed a panel of PDX from patients harboring or not germline BRCA1/2 mutations, namely from 26 primary or advanced breast cancer and 2 high-grade serous metastatic ovarian cancer (HGSOC). The antitumor activity of the PARP1/2 inhibitor olaparib as single agent (50 mg/kg) was assessed in all models. To study the mechanisms of acquired resistance, the olaparib-sensitive PDXs were exposed to olaparib for >100 days, until individual tumors regrew. The tumor's capacity to repair DNA double strand breaks was estimated by quantification of the BRCA1 and RAD51 nuclear foci in the S/G2-phase of the cell cycle. We investigated the correlation between the tumor's BRCA1/RAD51 foci formation and sensitivity to olaparib, and also identified potential genetic modifiers of PARPi sensitivity by targeted sequencing.

Results: Seven out of 28 PDX (25%) treated with single agent olaparib exhibited tumor regression or disease stabilization. Among the non-gBRCA PDX, BRCA1 hypermethylation or PALB2 mutation were present in olaparib-sensitive PDX. No genetic reversions in BRCA1/2 mutations were identified as the mechanism of olaparib resistance in gBRCA but BRCA1 foci formation was observed in 6 out of 10 resistant models (60%). Nuclear RAD51 foci formation correlated with PARPi resistance in twenty PDX models investigated, either with primary or acquired resistance. The duration of response was similar between gBRCA and non-gBRCA PDX. Acquired-resistance mechanisms involve restoration of HR functionality.

Conclusions: Our study highlights that somatic HR-deficiency is frequent in TNBC and provides the basis of sensitivity to PARPi. In our gBRCA (n=12) and non-gBRCA (n=16) PDX, reactivation of HR functionality measured as RAD51 foci formation is a frequent event that is associated with PARPi resistance.

Citation Format: Violeta Serra, Cristina Cruz, Marta Castroviejo, Sara Gutiérrez, Alba Llop, Alejandra Bruna, Beatriz Morancho, Ginevra Caratú, Ludmila Prudkin, Ana Vivancos, Paolo Nuciforo, Mark O'Connor, Jos Jonkers, Carlos Caldas, Joaquin Arribas, José Baselga, Isabel T. Rubio, Cristina Saura, Orland Díez, Judith Balmaña, Javier Cortés. Co-clinical trial of olaparib in breast and ovarian patient-derived tumor xenografts (PDX) enables the identification of response biomarkers. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B02.

Sunday, August 14, 2016 10:05 PM|Liang, L., Mercado-Uribe, I., Niu, N., Jiang, Y., Cheng, W., Broaddus, R., Bast, R., Mills, G., Sood, A. K., Liu, J.|Clinical Cancer Research recent issues|Labels: PARP, ovarian cancer

Ovarian cancer is the most lethal gynecological malignancy. The majority of ovarian cancer patients are diagnosed at an advanced stage of disease, and the lack of good early screening and diagnostic tests is one of the reasons for the low overall survival rate. Moreover, there is no good marker to predict patients' response to chemotherapy. Patient-derived xenografts (PDXs) have become the most promising preclinical model for gynecologic malignances. We have successfully established 22 PDX models derived from ovarian cancer patients' surgical specimens implanted into severe combined immunodeficient (SCID) mice, non-obese diabetic (NOD)-SCID or Nude mice. The majority of the PDX models were generated from patients' samples diagnosed with high-grade serous carcinoma including 3 with BRCA1/2 mutations, as well as less common types of ovarian cancers such as low-grade serous, endometrioid, mucinous carcinomas, and carcinosarcoma. PDXs have been established from solid masses as well as from ascites. We have optimized protocol for establishing ovarian PDXs including implantation and collection methods, tumor type (solid versus ascites), and type of mouse strains used. Using SCID mice, our success rate exceeded 80% and recent data indicated that the success rate in NOD/SCID mice was higher. The link between the pathology and PDX core, the "triage protocol" and ongoing PARP inhibitor trials will provide an important array of PDXs including pre- and post-treatment PDXs for exploration for biomarkers as well as for co-clinical trials to validate the utility of rational drug combinations. All models were validated using short tandem repeats (STR) and compared to the H&E and immunohistochemistry stains from the matching patient's tissue. We also examined the expression of B7-H4, a novel member of the B7 family immune checkpoint regulators, in 9 patient-derived xenografts (PDXs) of high-grade ovarian serous carcinoma. Our data showed that B7-H4 proteins were expressed in 8 of 9 PDX models of high-grade serous carcinoma, suggesting that PDXs may be useful for studying immunotherapy.

Citation Format: Li Liang, Imelda Mercado-Uribe, Na Niu, Yi Jiang, Wenjun Cheng, Russell Broaddus, Robert Bast, Gordon Mills, Anil K. Sood, Jinsong Liu. Establishment of Patient-Derived Xenograft (PDX) Models of Ovarian Cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B22.

Sunday, August 14, 2016 10:05 PM|Weroha, S. J.|Clinical Cancer Research recent issues|Labels: PARP, ovarian cancer

Ovarian cancer is the most lethal gynecologic cancer and the fifth most common cause of cancer death among women in the United States. Although there have been incremental improvements in progression free survival over the last several decades from advances in surgical technique and combination-chemotherapy strategies, overall survival has essentially remained unchanged. Although novel therapeutics have the potential to impact overall survival and lead to more cures, drug development in this area has been limited by the availability of clinically relevant models that recapitulate the molecular and phenotypic characteristics of primary ovarian cancers.

To overcome this barrier, we have developed primary patient derived xenograft (PDX) models from every consenting patient having primary debulking surgery at Mayo Clinic since 2010 (>550 unique patients). Fresh tissues are minced and injected intraperitoneally into severe combined immunodeficient (SCID) mice without enzymatic digestion or surgical implantation. The patient-to-mouse time is typically <1.5 hours and the engraftment rate is 73%.

Ovarian PDX models have demonstrated their utility as patient surrogates. The histologic diversity is representative of the population from which they are derived with high-grade serous comprising most of the models. However, the ovarian PDX bank also includes less-common subtypes, such as clear cell, mucinous, and carcinosarcoma. Histologic and genomic fidelity is maintained within early-passage tumors. Moreover, the patient's clinical response to carboplatin and paclitaxel (a standard front-line therapy for ovarian cancer) demonstrates high correlation to the matched PDX tumor response in vivo, supporting their relevance as patient surrogates.

The models have been used for preclinical drug development and biomarker validation. One example is the correlation between PARPi response in PDXs and their homologous recombination deficiency (HRD) score. All models with a low HRD score, <42, failed to respond to PARP inhibition while models with a high HRD score showed enrichment for response to a PARPi.

Ovarian PDXs are also being used to direct patient care in a clinical trial setting at all three Mayo Clinic sites (MN, FL, and AZ). Tumors are collected at the time of debulking surgery for heterotransplantation. Subsequent xenografts are treated with standard first-line chemotherapy, similar to their matched patient in the clinic, and then PDXs are treated with standard ovarian cancer second-line therapies: liposomal doxorubicin, topotecan, gemcitabine, and paclitaxel. When patients develop platinum-resistant recurrent cancer, the chemotherapy response in the PDX is used to direct therapy in the clinic.

Many challenges continue for ovarian cancer PDX models. The use of immunocompromised mice limits the ability to study the involvement of immunity in chemotherapy responsiveness. In addition, these models are not ideal for testing novel immunotherapies, such as the immune check point inhibitors. Further work to overcome these and other limitations are needed.

Citation Format: S. John Weroha. Ovatars in preclinical drug development and clinical trial for ovarian cancer patients. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA11.

Sunday, August 14, 2016 10:05 PM|Scaltriti, M.|Clinical Cancer Research recent issues|Labels: BRCA, PARP

Emergence of drug resistance is the main limitation for a durable response to therapy. The mechanisms of such resistance need to be uncovered in order to identify those patients that are more likely to respond and/or develop novel strategies to overcome tumor adaptation to therapy.

Patient-derived xenografts can be established from patients at any stage of their treatment. However, samples collected before the exposure to the pharmacological pressure (therapy-naïve) and tumors from patients that progressed to therapy after an initial response (acquired resistance) are preferable.

Of particular interest are the models derived from outliers; that are either patients unexpectedly refractory to a given therapy (e.g. BRCA-mut tumors not responding to PARP inhibitors or HER2-positive tumors not responding to anti-HER2 agents) or patients that exhibited an exceptional response (magnitude/durability) to specific targeted agents.

There are at least two advantages in using patient-derived material for this kind of studies. The availability of virtually limitless tissue allows deep genomic and proteomic analysis of tumor cells that supposedly resemble the clinical scenario. Moreover, the possibility to perpetuate these tumors is crucial to confirm the resistance phenotype and test novel and more efficacious therapeutic options.

In my presentation I will include several examples of how patient-derived models have helped demonstrating the genuineness of previously hypothesized mechanisms of resistance to targeted therapy and have been instrumental to test combinatorial strategies that resulted in remarkable antitumor activity. Furthermore, I will show that patient-derived models can also serve as tools to test novel "smart" drug delivery systems.

Citation Format: Maurizio Scaltriti. Studying drug resistance through PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA22.

Sunday, July 31, 2016 10:05 PM|Pratz, K. W., Koh, B. D., Patel, A. G., Flatten, K. S., Poh, W., Herman, J. G., Dilley, R., Harrell, M. I., Smith, B. D., Karp, J. E., Swisher, E. M., McDevitt, M. A., Kaufmann, S. H.|Clinical Cancer Research recent issues|Labels: PARP, MDS

Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo.

Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.

Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.

Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.

Monday, July 25, 2016 8:16 AM|Uchakina, O. N., Ban, H., Hostetler, B. J., McKallip, R. J.|Glycobiology - Advance Access|Labels: PARP, CML

In the current study we examined the ability of 4-methylumbelliferone (4-MU), which can inhibit hyaluronic acid synthesis, to sensitize K562 chronic myelogenous leukemia (CML) cells to doxorubicin therapy. Exposure of K562 cells to doxorubicin led to increased hyaluronic acid synthase (HAS) gene expression and increased levels of cell surface hyaluronic acid. Furthermore, exposure of K562 cells to exogenous HA caused resistance to doxorubicin-induced cell death. The combination of low dose 4-MU and doxorubicin led to increased apoptosis when compared to higher doses of any agent alone. Additionally, treatment with 4-MU led to a significant reduction in doxorubicin-induced increase in HA cell surface expression. Mechanistically, 4-MU treatment led to an increase in p38 activation and PARP cleavage. The role of p38 in 4-MU/doxorubicin-treated K562 cells was confirmed when p38 inhibitors led to protection from 4-MU/doxorubicin-induced apoptosis. Together, results from this study suggest that treatment with 4-MU increases the sensitivity of CML to chemotherapeutics by decreasing their HA-mediated resistance to apoptosis.

Wednesday, July 20, 2016 9:31 AM|Lok, B. H., Gardner, E. E., Schneeberger, V. E., Ni, A., Desmeules, P., Rekhtman, N., de Stanchina, E., Teicher, B. A., Riaz, N., Powell, S. N., Poirier, J. T., Rudin, C. M.|Clinical Cancer Research Online First Articles|Labels: PARP, lung cancer

Purpose: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. Experimental Design: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, were analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR-Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide were determined in vitro. In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models. Results: We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status. Conclusions: SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation.

Thursday, June 30, 2016 10:05 PM|Corcoran, N. M., Clarkson, M. J., Stuchbery, R., Hovens, C. M.|Clinical Cancer Research recent issues|Labels: P53, PARP

The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair–deficient tumors with drugs that take advantage of the fundamental differences between normal repair–proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132–7. ©2016 AACR.

Thursday, April 28, 2016 9:59 AM|GADDUCCI, A., GUERRIERI, M. E.|Anticancer Research recent issues|Labels: PARP, ovarian cancer

Homologous recombination (HR) and base excision repair (BER) are two of the major DNA-repair pathways. The proteins encoded by breast-related cancer antigen (BRCA) and poly(adenosine diphosphate-ribose) polymerases (PARP) are involved in HR and BER, respectively. Tumors with HR deficiency, including those in BRCA mutation carriers, are sensitive to BER blockade via PARP inhibitors. These represent novel therapeutic tools for HR-deficient ovarian cancer, able to improve progression-free survival of women with recurrent, platinum-sensitive disease in response to recent platinum-based chemotherapy. More research is needed to assesses whether inhibitors of PARP have any role as maintenance treatment after first-line chemotherapy and as palliative treatment of platinum-resistant disease. Germline BRCA testing should be offered to all patients with ovarian cancer, regardless of age and family history. HR deficiency has been observed not only in germline BRCA mutation carriers, but also in patients with somatic mutations or epigenetic silencing of BRCA, and with loss of function of other genes. Half of all high-grade ovarian carcinomas are HR-deficient, and additional biological and clinical investigations are strongly warranted to identify patients with this subset of tumors.

CONCLUSIONSThe numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, February 17, 2016 4:00 PM|Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: PARP, clinical trial
Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and are activated by DNA strand breaks. DNA damage from carboplatin has been associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. BMN 673 (Talazoparib) is an oral, selective PARP inhibitor. The phase I single agent maximum tolerated dose (MTD) of BMN 673 given once daily was 1mg po qd. Myelosuppresion was primary dose-limiting toxicity (DLT), including grade 3-4 thrombocytopenia. Carboplatin with paclitaxel is a current standard treatment for many solid tumors, including ovarian, bladder, upper gastrointestinal, breast and non-small cell lung cancer. Myelosuppression, including thrombocytopenia, is also seen with this co...
Thursday, February 11, 2016 4:00 PM|Familial Cancer|MedWorm: Cancer Therapy|Comments|Labels: PARP
Abstract Human cells have numerous repair mechanisms to counteract various insults incurred on the DNA. Any mutation in these repair mechanisms can lead to accumulation of DNA errors and carcinogenesis. This review aims to discuss the therapeutic options in the two most common DNA repair deficient cancer syndromes, namely Lynch syndrome (hereditary non-polyposis colorectal cancer) and breast cancer susceptibility gene (BRCA) associated ovarian and breast cancer. Deficiency in DNA repair mechanisms renders these tumors with increased sensitivity to platinum agents. There has been increasing amount of information on the utility of the defects in DNA repair as targets for cancer therapy in these syndromes. Novel therapies like poly (ADP-ribose) polymerase (PARP) inhibitors are one of...