The PARP inhibitor olaparib (AZD2281) as potent radiosensitizer of head and neck cancer cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16018-e16018 ◽  
Author(s):  
Inge Tinhofer ◽  
Mariya Boyko-Fabian ◽  
Franziska Niehr ◽  
Ulrich Keilholz ◽  
Volker Budach
Keyword(s):  
Dna Repair ◽  
Head And Neck ◽  
Cell Lines ◽  
Parp Inhibitor ◽  
Clonogenic Survival ◽  
Dose Effect ◽  
Parp Inhibition ◽  
Cross Resistance ◽  
Synergistic Activity ◽  
Potential Biomarker

e16018 Background: Current combined radiotherapy regimens for squamous cell carcinoma of the head and neck (SCCHN) are frequently not curative, necessitating novel therapeutic strategies. Inhibitors of poly(ADP-ribose) polymerases (PARPi), either alone or in combination with chemo- and radiotherapy have been shown to be highly active in tumor cells with intrinsic defects in DNA repair. Despite the frequent occurrence of genomic alterations in SCCHN cells also affecting their capacity of DNA repair the radiosensitizing potential of PARPi has not been addressed in detail so far. In this study, the efficacy of PARPi as radiosensitizer in SCCHN and possible mechanisms of cross-resistance between PARPi and cisplatin were evaluated. Methods: Usingthe clonogenic survival assay and a panel of 10 SCCHN cell lines the sensitivity of SCCHN cells to olaparib alone (0 to 500 nM) or in combination with irradiation (0 to 4 Gy) was determined. Survival fractions for given treatments were calculated on the basis of survival of untreated cells. In addition, the activity of cisplatin to inhibit clonogenic growth and its radiosensitizing potential was determined. From the dose-effect curves the IC50 values and the combinatory indices were calculated using the CalcuSyn Software. Results: In 9 of 10 cell lines, olaparib monotherapy showed significant inhibitory activity on clonogenic survival. Synergistic activity of olaparib in combination with irradiation was observed in all cell lines. No correlation between sensitivity of cells to olaparib and cisplatin (IC50 cisplatin vs IC50 olaparib: r2=0.042, p=.57; IC50 cisplatin vs CI [IR+olaparib]: r2=0.005, p=.95) was observed. Furthermore, the activity of olaparib was not dependent on the p53 genotype. Conclusions: The combination of PARPi with radiotherapy represents an active therapeutic regimen in SCCHN. The observed high activity of this combination even in cells with reduced sensitivity to cisplatin and p53 dysfunction suggests its clinical usefulness also in the group of patients with more aggressive disease and the second-line setting. Currently, detailed molecular characterization for identification of potential biomarker for tumor susceptibility to PARP inhibition is ongoing.

scholarly journals Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1918 ◽  
Author(s):  
Sanne Venneker ◽  
Alwine B. Kruisselbrink ◽  
Inge H. Briaire-de Bruijn ◽  
Yvonne de Jong ◽  
Andre J. van Wijnen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Idh Mutation ◽  
Mutation Status ◽  
Chondrosarcoma Cell ◽  
Idh Mutations

Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma.

PARP Inhibition (OLAPARIB) Enhance Melphalan and Nutlin-3a Sensitivity in TP53 Positive Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1846-1846
Author(s):  
Sinto Sebastian ◽  
Marta Chesi ◽  
Esteban Braggio ◽  
Leif Bergsagel ◽  
Keith Stewart ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Alkylating Agents ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Parp Cleavage ◽  
Wild Type ◽  
Combination Studies ◽  
Wild Type P53

Abstract Abstract 1846 Background The low frequency of TP53 (p53) alterations (<10%) in MM makes this tumor an ideal candidate for p53-activation therapies. Unfortunately, DNA alkylating agents (cyclophosphamide and melphalan), when used alone, cannot fully exploit p53 mediated apoptosis. It is currently unknown the extent to which DNA alkylating agents and p53 activating small molecules are activating functional p53 signaling to induce apoptosis in primary MM cells, because, p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. Emerging studies demonstrate that PARP activation and p53 poly(ADP-ribosyl)ation can negatively influence apoptosis induction but the exact molecular mechanisms are unknown. Methods For apoptosis and gene expression analysis 05 × 106 cells were incubated with 2.5 μM of melphalan, 10 μM of olaparib and 2.5 μM of nutlin-3a alone and/or combinations of melphalan with olparib and/or nutlin3a with olaprib for 24 to 72 hours before they were examined for cell death by the annexin-PI and FACS analysis. Gene and protein expression were measured by RT-PCR, western blot, and immunohistochemistry. For combination studies, cells were incubated with 0.194–50 μM of melphalan and 0.625–40 μM of either olaparib or ABT-888 for 72 hours. p53 knock-down performed by lentiviral mediated shRNA. Vk*MYC mice with significant gammopathy (>20g/l on SPEP) used for in-vivo drug combination studies. Results Preliminary results support our principle hypothesis that, a PARP inhibitor (olaparib) enhanced Melphalan sensitivity in wild type p53 MM cell lines H929 and MM1S but not in p53 mutated or homozygously deleted cell lines U266 and KMS11, respectively. Moreover, we demonstrate that p53 knock-down decreased the synergistic effect of combining a PARP inhibitor with melphalan and Nutlin-3a. Again, combining a PARP inhibitor with the DNA alkylating agent melphalan induced clear PARP cleavage, a signature of apoptosis in wild type p53 MM cell lines H929 and MM1S. No significant PARP cleavage was observed after melphalan or olaparib treatment alone in H929 and MMIS. As expected, the p53 mutant cell line U266 did not show any PARP cleavage and p21 up-regulation after both drug treatments. Here we propose that the hyper-activated p53 from PARP inhibition along with DNA alkylating agents (melphalan) and/or p53 activating agents (nutlin-3a) result in better responses. Finally, in a murine xenograft model of human MM, olaparib potentiated melphalan activity in vivo, with significant reduction in M spike level. Conclusion Our studies indicate that DNA alkylating agents activate wild type p53, but leads to DNA repair and cell survival and this can be abolished by PARP inhibition in wild type p53 expressing MM cases. Moreover, our study also found that olaparib, and ABT-888 - PARP1 inhibitors currently in clinical trials - display different dose responses in MM cell lines and in the abilities of individual PARP inhibitors to sensitize MM cell lines to melphalan varied to a great extent in a cell context- and cell line specific manner. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Buck ◽  
Patrick J. C. Dyer ◽  
Hilary Hii ◽  
Brooke Carline ◽  
Mani Kuchibhotla ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Combination Therapy ◽  
Cellular Response ◽  
Molecular Subtype ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibition ◽  
Preclinical Model ◽  
Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

scholarly journals DNA Repair in Lymphoblastoid Cell Lines From Patients With Head and Neck Cancer

1999 ◽  
Vol 125 (2) ◽  
pp. 185 ◽  
Author(s):  
Erich M. Sturgis ◽  
Gary L. Clayman ◽  
Yongli Guan ◽  
Zhaozheng Guo ◽  
Qingyi Wei
Keyword(s):  
Dna Repair ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cell Lines ◽  
Neck Cancer ◽  
Lymphoblastoid Cell Lines

scholarly journals Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9034
Author(s):  
Cristina Nieto-Jimenez ◽  
Ana Alcaraz-Sanabria ◽  
Sandra Martinez-Canales ◽  
Veronica Corrales-Sanchez ◽  
Juan Carlos Montero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cell Lines ◽  
Parp Inhibitor ◽  
Clinical Development ◽  
Therapeutic Options ◽  
Cancer Drug ◽  
Platinum Resistance ◽  
Synergistic Activity ◽  
Basal Like Breast Cancer

Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.

scholarly journals Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency

2016 ◽  
pp. e259-e268 ◽  
Author(s):  
Rebecca S. Kristeleit ◽  
Rowan E. Miller ◽  
Elise C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Molecular Therapy ◽  
Parp Inhibition ◽  
Gynecologic Cancers ◽  
Brca Mutations ◽  
Individual Gene

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed “ BRCAness”). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.

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.

Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 203-203
Author(s):  
R. Tuli ◽  
A. Surmak ◽  
A. Blackford ◽  
A. Leubner ◽  
E. M. Jaffee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Pancreatic Cancer Cells ◽  
Synergistic Mechanism ◽  
Radiation Induced ◽  
Parp 1

203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p<0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.

PARPi in PCa results in decreased availability of DNA repair factors.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 301-301
Author(s):  
Matthew Joseph Schiewer ◽  
Karen E. Knudsen
Keyword(s):  
Dna Repair ◽  
Enzymatic Activity ◽  
Disease Progression ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Clinical Trial Data ◽  
Parp Inhibition ◽  
Transcriptional Regulatory ◽  
Parp 1

301 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).

A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of oral COH29, a novel ribonucleotide reductase (RNR) inhibitor in adult patients (pts) with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2600-TPS2600
Author(s):  
Joseph Chao ◽  
Timothy W. Synold ◽  
Paul Henry Frankel ◽  
Joanne E. Mortimer ◽  
Vincent M. Chung ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase I ◽  
Cell Lines ◽  
Small Molecule ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Objective Response ◽  
Dose Finding ◽  
Parp Inhibition ◽  
Peripheral Blood Mononuclear

TPS2600 Background: Human RNR catalyzes the rate-limiting step in the formation of deoxyribonucleotide triphosphates (dNTPs) necessary for DNA repair and replication. Rapidly dividing tumor cells are especially sensitive to RNR inhibition due to elevated dNTP requirements. Overexpression of the RNR RRM2 subunit is also associated with neoplasia, metastasis, and poor prognosis. COH29 is an aromatically substituted thiazole compound that is a novel small molecule inhibitor of RNR activity, and exhibits unique mechanisms and target specificity that overcomes the weaknesses of other small molecule RNR inhibitors. Preclinically, it is more potent than hydroxyurea and gemcitabine, and is not associated with iron chelating-related toxicities such as hypoxia. Cell lines deficient in BRCA1 also exhibit greater sensitivity to COH29 than BRCA1 wildtype cell lines, implicating inhibition of DNA repair mechanisms in line with PARP inhibitors. Methods: In this Phase I, single site, dose escalation, safety study pts will receive oral COH29 twice a day for 21 days of a 28-day cycle. Eligible pts are age ≥ 18 years, ECOG ≤ 2, able to take oral medication, have adequate organ and marrow function, and diagnosed with any solid tumor refractory to standard therapies. Dose escalation will be pursued utilizing a Simon’s accelerated titration design, which allows skipping of dose levels (dose doubling) during the accelerated dose-finding phase. Primary objectives are to determine the maximum tolerated dose of COH29, toxicities per CTCAEv4, and PKs. Secondary objectives include assessment of objective response per RECIST 1.1 every 2 cycles. PD assessment includes measurement of plasma CK18 levels to determine degree of cellular apoptosis, evaluation of dNTP pool levels in peripheral blood mononuclear cells (PBMCs) to evaluate RNR inhibition, as well as measurement of PAR expression in PBMCs to assess PARP inhibition. Quantitation of tumor RRM2 expression using dual-color immunohistochemistry will be explored as a predictive biomarker of anti-tumor response to COH29. Clinical trial information: NCT02112565.

Sign in / Sign up

Export Citation Format

Share Document