Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 2314 word(s) 2314 2021-02-20 04:08:23 |
2 format correct -21 word(s) 2293 2021-03-03 03:02:57 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Konstantinidou, G. Targeted Therapies for Pancreatic Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/7671 (accessed on 14 April 2024).
Konstantinidou G. Targeted Therapies for Pancreatic Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/7671. Accessed April 14, 2024.
Konstantinidou, Georgia. "Targeted Therapies for Pancreatic Cancer" Encyclopedia, https://encyclopedia.pub/entry/7671 (accessed April 14, 2024).
Konstantinidou, G. (2021, March 02). Targeted Therapies for Pancreatic Cancer. In Encyclopedia. https://encyclopedia.pub/entry/7671
Konstantinidou, Georgia. "Targeted Therapies for Pancreatic Cancer." Encyclopedia. Web. 02 March, 2021.
Targeted Therapies for Pancreatic Cancer
Edit

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies.

pancreatic ductal adenocarcinoma therapies DNA repair tumor microenvironment epigenetic alterations key mutations autophagy immunotherapy

1. Introduction

Pancreatic ductal adenocarcinoma (thereafter PCa) remains one of the deadliest malignancies with a 5-year overall survival (OS) of only 9% in 2020 [1]. The reason for this lies on the fact that, due to the late diagnosis, about 80% of patients arriving to the clinic have already locally advanced and unresectable PCa as a result of local invasion of adjacent structures. Based on the tumor stage at the time of diagnosis, PCa can be treated with surgery, chemotherapy, radiation therapy, and targeted therapy with different recommendations [2][3][4]. At a resectable PCa setting, surgery can have a curative (when all the tumor can be removed) purpose. According to recent clinical practice guidelines of the American Society of Clinical Oncology, modified FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin, thereafter mFOLFIRINOX) must be the preferred adjuvant therapy for patients with pancreatic adenocarcinoma who have undergone an R0 or R1 resection and have not received prior neoadjuvant chemotherapy [5]. The term “modified” refers to the reduction of irinotecan from 180 to 150 mg/m2 and the exclusion of the 5-FU bolus due to the emergence of adverse effects of FOLFIRINOX. Moreover, in the adjuvant/post-operative setting, conventionally fractionated radiation is recommended for patients with high-risk features such as positive lymph nodes and margins. For patients with locally advanced and metastatic disease (unresectable PCa), systemic chemotherapy, generally mFOLFIRINOX or gemcitabine/nab-paclitaxel combination, followed by radiation therapy is recommended, and depending on the presence of alterations, including specific genetic mutations, mismatch repair deficiency, or high microsatellite instability, may receive additional targeted therapies. However, in such advanced stage and due to the aggressive cell biology of PCa with continuing therapy resistance, the available treatment options are not sufficient for curative outcomes. While chemotherapy clearly improves the OS of PCa patients at the preoperative and postoperative setting, radiotherapy is subjected to controversy due to conflicting clinical trial results and its association with a narrow therapeutic index. The impact of radiotherapy in the management of PCa has been extensively reviewed elsewhere [6].

Aside from the general aging of our society, obesity and type-2 diabetes play a role in the etiology of PCa. In this case, a chronic low-grade inflammation may be a potential mechanism linking obesity to increased PCa incidence and progression [7][8][9]. Moreover, lifestyle habits, including alcohol abuse and tobacco use appear to contribute to PCa development [10]. Lastly, there are some genetic syndromes characterized by specific mutations such as BRCA1, BRCA2 (Breast and ovarian cancer syndrome), ATM (Ataxia telangiectasia), STK11 (Peutz-Jeghers syndrome), PRSS1 (hereditary pancreatitis), MLH1, and MSH2/6 (Lynch syndrome) that are associated with PCa for a subgroup of patients, representing additional risk factors [11]. A deeper understanding of the pathology of PCa may explain therapeutic resistance, survival differences, and responses to specific therapies. The genetic landscape of PCa is characterized by somatic mutations in one or more of the four major genes: KRAS, CDKN2A, TP53, and SMAD4 [12]. Besides these mutations, the development of PCa depends on the tumor microenvironment (TME). Targeting single deregulated pathways is often ineffective owing to redundant signaling and complex crosstalk. Moreover, the high degree of inter-tumoral genetic heterogeneity of PCa suggests that it is unlikely that a single targeted therapy will work [13][14].

2. Targeting DNA Repairing Deficiency and Microsatellite Instability

Genomic instability is a key feature of almost all human cancers [15]. Such modifications benefit the clonal growth of cancer cells, including improvements in gene copy numbers, rearrangements, and mutations. Nevertheless, these same defects often produce cancer cell vulnerabilities that could be used for anticancer therapies. A substantial population of PCa patients harbors germline or somatic mutations in genes that are involved in the DNA damage repair (DDR) pathway, such as BRCA1/2 and ATM [16], suggesting that these patients may benefit from personalized targeted therapies. Moreover, PCa cells may be selectively sensitive to DDR inhibitors because KRAS mutations, which are present in 95% of PCa cases, are associated with increased replication stress due to depletion of nucleotide pools [17] and the slowing of replication fork activity [18].

2.1. PARP Inhibitors

Poly (ADP-ribose) polymerase (PARP) enzymes detect and bind to single-strand DNA breaks (SSB), leading to the recruitment of hundreds of proteins to repair the SSBs. However, if SSBs are not repaired, they cause stall of replications forks and eventually progress to double-strand breaks, which are highly cytotoxic to cells. Thus, cancer cells with mutations that prevent homologous recombination repair, such as BRCA1/2 loss-of-function mutations, are often synthetically lethal with PARP inhibitors due to significantly lower DDR [19]. A phase II clinical trial with olaparib, a small molecule PARP inhibitor, in a small cohort of BRCA1/2 mutated advanced PCa patients with gemcitabine resistance, evidenced a tumor response rate of 50.0% (4/8 patients), while 25% showed stable disease ≥ 8 weeks with a median overall survival (OS) of 9.8 months [20]. Similarly, a phase III clinical trial with olaparib that included 154 metastatic PCa patients with a germline BRCA1 or BRCA2 mutation resulted in a median progression-free survival (PFS) of 7.4 months in the olaparib group vs. 3.8 months of the placebo group [21]. Thus, the documented efficacy of PARP inhibitors in PCa patients with germline BRCA1 or BRCA2 mutation underscores the importance of germline testing for all patients with PCa.

In addition to PARP inhibitors alone, several trials are currently underway to evaluate PARP inhibitor combinations with other classes of therapies causing DNA damage in PCa patients. However, in >80% of patients, PARP inhibitors, when combined with chemotherapy, including olaparib plus gemcitabine and olaparib plus irinotecan or cisplatin, showed substantial toxicity [22][23]. Clinical trials designed to assess the effectiveness of certain PARP inhibitor combinations of chemotherapy and/or dose-reduced chemotherapy will help decide whether or not such combinations will play a role in providing therapeutic efficacy in PCa patients.

2.2. ATM Inhibition

In contrast to PARP inhibitors, the use of other DDR inhibitors is currently restricted to early clinical studies. Ataxia Telangiectasia Mutated (ATM) is a serine/threonine kinase involved in DDR signaling and it is one of the most commonly mutated DDR genes, with a number of somatic or germline mutations identified in PCa [24][25]. A mouse model of ATM deficient PCa evidenced an increased number of pancreatic intraepithelial precursor lesions, fibrosis, and a greater degree of epithelial to mesenchymal transition compared to the control mice, suggesting a role in PCa progression [26]. ATM inhibitors such as AZD0156 in combination with olaparib, irinotecan, or fluorouracil in patients with advanced solid tumors are currently in phase I clinical trials (NCT02588105). Cancer cells may compensate the loss of ATM by upregulating ATR, indicating that ATR inhibitors may display efficacy in ATM-deficient tumors, including PCa. However, ATM-deficient PCa cell lines undergo cell death only when incubated with olaparib plus AZD6738, an ATR inhibitor, but neither agent alone [27]. Thus, patients with ATM deficient PCa may benefit from combination therapies targeting PARP and ATR.

Intriguingly, recent preclinical data showed that the addition of DNA-PK inhibitors with PARP and ATR inhibitors provide synergistic antitumor effects in both ATM-deficient and ATM-proficient cells [28]. If this approach turns out to be feasible in the clinic, it will considerably extend the target population that can benefit from such combination therapies.

2.3. ATR Inhibition

ATR is one of the primary targets of DDR inhibitors since both SSBs and double-strand DNA breaks (DSBs) are the main regulatory features of ATR [29]. There are currently five ongoing clinical trials assessing ATR targeting compounds: AZD6738 (NCT02630199, NCT03669601), M6620 (NCT03718091), M4344 (NCT02278250), and BAY1895344 (NCT03188965). In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell cycle arrest, and strongly induced replication stress. Interestingly, the combination of AZD6738 and gemcitabine induced tumor regression in a subgroup of tumors in the KRASG12D; p53R172H; Pdx-cre (KPC) mouse model in vivo [30]. Similar to human PCa, KPC mouse tumors are known to be refractory to therapy, suggesting that the combination of ATR with chemotherapy may be effective in a subset of human PCa patients. M6620 is the first ATR inhibitor tested for monotherapy and combined with various chemotherapies, including topotecan, carboplatin, gemcitabine, and cisplatin [31][32][33]. M6620 monotherapy was well tolerated without observation of dose limiting toxicities and the combination with carboplatin showed clinical activity in patients with advanced solid tumors [33]. Nevertheless, chemotherapy combinations were associated with higher rates of bone marrow toxicity which required M6620 dose reduction. Thus, when used in combination with systemic DNA damaging chemotherapy, it is necessary to optimize the dose/frequency of ATR inhibitors to allow normal tissue recovery. More ongoing phase I clinical trials aim at determining the safety and maximum tolerated dose of ATR inhibitors in combination with chemotherapy in patients with advanced solid tumors. Of these, NCT02630199 and NCT03669601 are testing AZD6738 in combination with paclitaxel and gemcitabine, respectively, while the NCT02278250 aims at testing M4344 in combination with carboplatin.

2.4. DNA-PK Inhibition

The DNA-dependent protein kinase (DNA-PK) is involved in the non-homologous end joining (NHEJ) pathway [34]. This class of drugs is particularly important in combination with ionizing radiation (IR) because NHEJ is the prevailing repair mechanism for IR-induced DNA double-strand breaks [35]. Indeed, DNA-PK genetic deficiencies sensitize cells to IR and other DSB-inducing agents [36]. M3814 (peposertib), a highly potent and selective inhibitor of DNA-PK, sensitized pancreatic cancer cells to IR in vitro and provided complete tumor regression upon treatment with IR in vivo [37]. In the clinical setting, M3814 has been tested in a phase I clinical trial (NCT02316197) in which it was well-tolerated when given orally as a single agent in doses up to 400 mg BID [38]. Based on the promising preclinical and clinical trials, M3814 has progressed into a phase I/II clinical testing in combination with hypofractionated radiation therapy for the treatment of unresectable locally advanced PCa (NCT04172532). This study, which is currently recruiting participants, is expected to be concluded in 2024.

2.5. CHK1/2 Inhibition

Cell cycle progression is monitored by mechanisms that control the transition from quiescence (G0) to proliferation, ensuring genetic transcript fidelity. Checkpoint kinase 1 (CHK1) and CHK2 are serine/threonine protein kinases that are part of the recognition of DNA damage. CHK1 is an important signal transducer and the trigger of G2 checkpoint activation, while CHK2 is involved in the repair of DNA, cell cycle, and apoptosis in DDR. CHEK2 gene mutations have been identified in a wide variety of cancers, including PCa [39]. A CHK1/2 inhibitor, AZD7762, alone or in combination with gemcitabine significantly sensitized PCa cells (MiaPaCa-2) to radiation. Interestingly, the radiosensitization was associated with abrogation of the G2 checkpoint, inhibition of Rad51 focus formation, inhibition of homologous recombination repair, and persistent gamma-H2AX expression [40]. However, AZD7762 in combination with gemcitabine provided only a partial objective response in gemcitabine-naïve patients (NCT00413686). Moreover, AZD7762 was found to be cardiotoxic, which occurred at doses as low as 30 mg and had to be stopped [41][42].

A phase I/II trial with rabusertib (LY2603618), a highly selective CHK1 inhibitor, assessed whether combination with gemcitabine could prolong OS compared to gemcitabine alone in 99 patients with unresectable PCa (NCT00839332). The results from this study evidenced that the combination of rabusertib with gemcitabine did not confer a greater survival advantage compared to gemcitabine alone [43]. Recently, another preclinical study showed that prexasertib (LY2606368), a drug currently in phase I clinical trials, increases the sensitivity of PCa cells to gemcitabine and S-1 (an orally available fluoropyrimidine derivative) [44]. Prexasertib is currently being evaluated in combination with olaparib (NCT03057145) or multiple other targeted drugs (NCT02124148) in advanced solid tumors.

Overall, the lack of obvious clinical efficacy and the reported increased cardiotoxicity warrant further studies to clearly assess whether CHK1 inhibitors can be used for PCa therapy.

2.6. Wee1

The Wee1 protein kinase phosphorylates CDK1Tyr15, resulting in G2/M checkpoint activation [45]. Thus, Wee1 inhibition prevents initiation of G2 checkpoints, causing transformed cells with damaged DNA to go through mitosis and cell death. There are multiple completed or ongoing clinical trials with Wee1 inhibitors in many tumor types that have been extensively reviewed by Ghelli Luserna di Rorà et al. [46]. One of these clinical trials examined AZD1775, a Wee1 kinase inhibitor, as monotherapy or in combination with chemotherapy (gemcitabine, cisplatin, or carboplatin) in patients with refractory solid tumors (NCT00648648). Of 176 patients that were given combination therapy, 94 (53%) had stable disease and 17 (10%) achieved a partial response. Interestingly, the response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33) [47]. In PDAC, AZD1775 was tested in a dose escalation study alone or combined with gemcitabine (+radiation) in a cohort of 34 patients with locally advanced unresectable PCa (NCT02037230). In this trial, the combination of AZD1775 with gemcitabine and radiation resulted in an OS of 22 months compared to the 11.9 to 13.6 months of gemcitabine/radiation alone [48]. Currently, the benefits of adding the AZD1775 into a gemcitabine + nanoparticle albumin-bound (nab)-paclitaxel are being evaluated in a phase I/II clinical trial in patients with previously untreated unresectable or metastatic PCa (NCT02194829).

Preclinical evidence has indicated that Wee1 inhibitors show synergistic effects when combined with histone deacetylase (HDAC) inhibitors [49], proteasome inhibitors [50], tyrosine kinase inhibitors [51], anti-apoptotic protein inhibitors (enhance dependency on BCL-2 and/or MCL-1 inhibition) [52], and mammalian (or mechanic) target of rapamycin (mTOR) inhibitors [53]. This latter study is particularly noteworthy for PCa as mTOR inhibition was found to synergize with Wee1 inhibition in KRAS mutant tumors. Future research is necessary to assess whether the combination of Wee1 with mTOR inhibitors may be an effective therapeutic strategy for the treatment of PCa.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30.
  2. Sohal, D.P.S.; Kennedy, E.B.; Cinar, P.; Conroy, T.; Copur, M.S.; Crane, C.H.; Garrido-Laguna, I.; Lau, M.W.; Johnson, T.; Krishnamurthi, S.; et al. Metastatic Pancreatic Cancer: ASCO Guideline Update. J. Clin. Oncol. 2020, 38, 3217–3230.
  3. Balaban, E.P.; Mangu, P.B.; Yee, N.S. Locally Advanced Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary. J. Oncol. Pract. 2017, 13, 265–269.
  4. Khorana, A.A.; Mangu, P.B.; Berlin, J.; Engebretson, A.; Hong, T.S.; Maitra, A.; Mohile, S.G.; Mumber, M.; Schulick, R.; Shapiro, M.; et al. Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. Oncol. 2017, 35, 2324–2328.
  5. Khorana, A.A.; McKernin, S.E.; Berlin, J.; Hong, T.S.; Maitra, A.; Moravek, C.; Mumber, M.; Schulick, R.; Zeh, H.J.; Katz, M.H.G. Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update. J. Clin. Oncol. 2019, 37, 2082–2088.
  6. Hall, W.A.; Goodman, K.A. Radiation therapy for pancreatic adenocarcinoma, a treatment option that must be considered in the management of a devastating malignancy. Radiat Oncol. 2019, 14, 114.
  7. Berrington de Gonzalez, A.; Sweetland, S.; Spencer, E. A meta-analysis of obesity and the risk of pancreatic cancer. Br. J. Cancer 2003, 89, 519–523.
  8. Incio, J.; Liu, H.; Suboj, P.; Chin, S.M.; Chen, I.X.; Pinter, M.; Ng, M.R.; Nia, H.T.; Grahovac, J.; Kao, S.; et al. Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy. Cancer Discov. 2016, 6, 852–869.
  9. Elena, J.W.; Steplowski, E.; Yu, K.; Hartge, P.; Tobias, G.S.; Brotzman, M.J.; Chanock, S.J.; Stolzenberg-Solomon, R.Z.; Arslan, A.A.; Bueno-de-Mesquita, H.B.; et al. Diabetes and risk of pancreatic cancer: A pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control. 2013, 24, 13–25.
  10. Ryan, D.P.; Hong, T.S.; Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 2014, 371, 1039–1049.
  11. Kleeff, J.; Korc, M.; Apte, M.; la Vecchia, C.; Johnson, C.D.; Biankin, A.V.; Neale, R.E.; Tempero, M.; Tuveson, D.A.; Hruban, R.H.; et al. Pancreatic cancer. Nat. Rev. Dis. Primers 2016, 2, 16022.
  12. Carr, R.M.; Fernandez-Zapico, M.E. Toward personalized TGFβ inhibition for pancreatic cancer. EMBO Mol. Med. 2019, 11, e11414.
  13. Biankin, A.V.; Maitra, A. Subtyping Pancreatic Cancer. Cancer Cell 2015, 28, 411–413.
  14. Collisson, E.A.; Sadanandam, A.; Olson, P.; Gibb, W.J.; Truitt, M.; Gu, S.; Cooc, J.; Weinkle, J.; Kim, G.E.; Jakkula, L.; et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 2011, 17, 500–503.
  15. Schmitt, A.; Feldmann, G.; Zander, T.; Reinhardt, H.C. Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma. Oncol. Res. Treat. 2018, 41, 619–625.
  16. Perkhofer, L.; Gout, J.; Roger, E.; de Almeida, F.K.; Simoes, C.B.; Wiesmuller, L.; Seufferlein, T.; Kleger, A. DNA damage repair as a target in pancreatic cancer: State-of-the-art and future perspectives. Gut 2021, 70, 606–617.
  17. Aird, K.M.; Zhang, G.; Li, H.; Tu, Z.; Bitler, B.G.; Garipov, A.; Wu, H.; Wei, Z.; Wagner, S.N.; Herlyn, M. et al. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Rep. 2013, 3, 1252–1265.
  18. Maya-Mendoza, A.; Ostrakova, J.; Kosar, M.; Hall, A.; Duskova, P.; Mistrik, M.; Merchut-Maya, J.M.; Hodny, Z.; Bartkova, J.; Christensen, C.; et al. Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. Mol. Oncol. 2015, 9, 601–616.
  19. Lord, C.J.; Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 2016, 16, 110–120.
  20. Kaufman, B.; Shapira-Frommer, R.; Schmutzler, R.K.; Audeh, M.W.; Friedlander, M.; Balmaña, J.; Mitchell, G.; Fried, G.; Stemmer, S.M.; Hubert, A.; et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 2015, 33, 244–250.
  21. Golan, T.; Hammel, P.; Reni, M.; van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.O.; Hochhauser, D.; Arnold, D.; Oh, D.Y.; et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019, 381, 317–327.
  22. Yarchoan, M.; Myzak, M.C.; Johnson, B.A.; 3rd; de Jesus-Acosta, A.; Le, D.T.; Jaffee, E.M.; Azad, N.S.; Donehower, R.C.; Zheng, L.; Oberstein, P.E.; et al. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget 2017, 8, 44073–44081.
  23. Bendell, J.; O'Reilly, E.M.; Middleton, M.R.; Chau, I.; Hochster, H.; Fielding, A.; Burke, W.; Burris, H., III. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer. Ann. Oncol. 2015, 26, 804–811.
  24. Armstrong, S.A.; Schultz, C.W.; Azimi-Sadjadi, A.; Brody, J.R.; Pishvaian, M.J. ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications. Mol. Cancer Ther. 2019, 18, 1899–1908.
  25. Kamphues, C.; Bova, R.; Bahra, M.; Klauschen, F.; Muckenhuber, A.; Sinn, B.V.; Warth, A.; Goeppert, B.; Endris, V.; Neuhaus, P.; et al. Ataxia-telangiectasia-mutated protein kinase levels stratify patients with pancreatic adenocarcinoma into prognostic subgroups with loss being a strong indicator of poor survival. Pancreas 2015, 44, 296–301.
  26. Russell, R.; Perkhofer, L.; Liebau, S.; Lin, Q.; Lechel, A.; Feld, F.M.; Hessmann, E.; Gaedcke, J.; Güthle, M.; Zenke, M.; et al. Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition. Nat. Commun. 2015, 6, 7677.
  27. Jette, N.R.; Kumar, M.; Radhamani, S.; Arthur, G.; Goutam, S.; Yip, S.; Kolinsky, M.; Williams, G.J.; Bose, P.; Lees-Miller, S.P. ATM-Deficient Cancers Provide New Opportunities for Precision Oncology. Cancers 2020, 12, 687.
  28. Gout, J.; Perkhofer, L.; Morawe, M.; Arnold, F.; Ihle, M.; Biber, S.; Lange, S.; Roger, E.; Kraus, J.M.; Stifter, K.; et al. Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer. Gut 2020.
  29. Sundar, R.; Brown, J.; Russo, A.I.; Yap, T.A. Targeting ATR in cancer medicine. Curr. Probl. Cancer 2017, 41, 302–315.
  30. Wallez, Y.; Dunlop, C.R.; Johnson, T.I.; Koh, S.B.; Fornari, C.; Yates, J.W.T.; Fernandez, S.B.d.; Lau, A.; Richards, F.M.; Jodrell, D.I. The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression. Mol. Cancer Ther. 2018, 17, 1670–1682.
  31. O'Carrigan, B.; de Miguel Luken, M.; Papadatos-Pastos, D.; Brown, J.; Tunariu, N.; Perez-Lopez, R.; Ganegoda, M.; Riisnaes, R.; Figueiredo, I.; Carreira, S.; et al. Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies. J. Clin. Oncol. 2016, 34, 2504–2504.
  32. Plummer, E.R.; Dean, E.J.; Evans, T.R.J.; Greystoke, A.; Herbschleb, K.; Ranson, M.; Brown, J.; Zhang, Y.; Karan, S.; Pollard, J.; et al. Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792). J. Clin. Oncol. 2016, 34 (Suppl. S15), 2513.
  33. Yap, T.A.; O'Carrigan, B.; Penney, M.S.; Lim, J.S.; Brown, J.S.; Luken, M.J.d.; Tunariu, N.; Perez-Lopez, R.; Rodrigues, D.N.; Riisnaes, R.; et al. Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2020, 38, 3195–3204.
  34. Brown, J.S.; O'Carrigan, B.; Jackson, S.P.; Yap, T.A. Targeting DNA Repair in Cancer: Beyond PARP Inhibitors. Cancer Discov. 2017, 7, 20–37.
  35. Willers, H.; Dahm-Daphi, J.; Powell, S.N. Repair of radiation damage to DNA. Br. J. Cancer 2004, 90, 1297–1301.
  36. Lees-Miller, S.P.; Godbout, R.; Chan, D.W.; Weinfeld, M.; Day, R.S., III; Barron, G.M.; Allalunis-Turner, J. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science 1995, 267, 1183–1185.
  37. Zenke, F.T.; Zimmermann, A.; Sirrenberg, C.; Dahmen, H.; Kirkin, V.; Pehl, U.; Grombacher, T.; Wilm, C.; Fuchss, T.; Amendt, C.; et al. Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models. Mol. Cancer Ther. 2020, 19, 1091–1101.
  38. van Bussel, M.T.J.; Awada, A.; de Jonge, M.J.A.; Mau-Sorensen, M.; Nielsen, D.; Schoffski, P.; Verheul, H.M.W.; Sarholz, B.; Berghoff, K.; el Bawab, S.; et al. A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. Br. J. Cancer 2020, 1–8.
  39. Hu, C.; Hart, S.N.; Bamlet, W.R.; Moore, R.M.; Nandakumar, K.; Eckloff, B.W.; Lee, Y.K.; Petersen, G.M.; McWilliams, R.R.; Couch, F.J. Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol. Biomark. Prev. 2016, 25, 207–211.
  40. Morgan, M.A.; Parsels, L.A.; Zhao, L.; Parsels, J.D.; Davis, M.A.; Hassan, M.C.; Arumugarajah, S.; Hylander-Gans, L.; Morosini, D.; Simeone, D.M.; et al. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res. 2010, 70, 4972–4981.
  41. Seto, T.; Esaki, T.; Hirai, F.; Arita, S.; Nosaki, K.; Makiyama, A.; Kometani, T.; Fujimoto, C.; Hamatake, M.; Takeoka, H.; et al. Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours. Cancer Chemother Pharm. 2013, 72, 619–627.
  42. Sausville, E.; Lorusso, P.; Carducci, M.; Carter, J.; Quinn, M.F.; Malburg, L.; Azad, N.; Cosgrove, D.; Knight, R.; Barker, P.; et al. Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother Pharm. 2014, 73, 539–549.
  43. Laquente, B.; Lopez-Martin, J.; Richards, D.; Illerhaus, G.; Chang, D.Z.; Kim, G.; Stella, P.; Richel, D.; Szcylik, C.; Cascinu, S.; et al. A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. BMC Cancer 2017, 17, 137.
  44. Morimoto, Y.; Takada, K.; Takeuchi, O.; Takagi, A.; Watanabe, K.; Hirohara, M.; Hamamoto, T.; Masuda, Y. Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S‑1. Oncol. Rep. 2020, 43, 689–699.
  45. Aarts, M.; Sharpe, R.; Garcia-Murillas, I.; Gevensleben, H.; Hurd, M.S.; Shumway, S.D.; Toniatti, C.; Ashworth, A.; Turner, N.C. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2012, 2, 524–539.
  46. Ghelli Luserna di Rora, A.; Cerchione, C.; Martinelli, G.; Simonetti, G. A WEE1 family business: Regulation of mitosis, cancer progression, and therapeutic target. J. Hematol. Oncol. 2020, 13, 126.
  47. Leijen, S.; van Geel, R.M.; Pavlick, A.C.; Tibes, R.; Rosen, L.; Razak, A.R.; Lam, R.; Demuth, T.; Rose, S.; Lee, M.A.; et al. Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2016, 34, 4371–4380.
  48. Cuneo, K.C.; Morgan, M.A.; Sahai, V.; Schipper, M.J.; Parsels, L.A.; Parsels, J.D.; Devasia, T.; Al-Hawaray, M.; Cho, C.S.; Nathan, H.; et al. Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer. J. Clin. Oncol. 2019, 37, 2643–2650.
  49. Zhou, L.; Zhang, Y.; Chen, S.; Kmieciak, M.; Leng, Y.; Lin, H.; Rizzo, K.A.; Dumur, C.I.; Ferreira-Gonzalez, A.; Dai, Y.; et al. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. Leukemia 2015, 29, 807–818.
  50. Barbosa, R.S.S.; Dantonio, P.M.; Guimaraes, T.; de Oliveira, M.B.; Alves, V.L.F.; Sandes, A.F.; Fernando, R.C.; Colleoni, G.W.B. Sequential combination of bortezomib and WEE1 inhibitor, MK-1775, induced apoptosis in multiple myeloma cell lines. Biochem. Biophys. Res. Commun. 2019, 519, 597–604.
  51. Ghelli Luserna Di Rora, A.; Beeharry, N.; Imbrogno, E.; Ferrari, A.; Robustelli, V.; Righi, S.; Sabattini, E.; Falzacappa, M.V.V.; Ronchini, C.; Testoni, N.; et al. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia. J. Hematol. Oncol. 2018, 11, 99.
  52. de Jong, M.R.W.; Langendonk, M.; Reitsma, B.; Herbers, P.; Nijland, M.; Huls, G.; van den Berg, A.; Ammatuna, E.; Visser, L.; van Meerten, T. WEE1 Inhibition Enhances Anti-Apoptotic Dependency as a Result of Premature Mitotic Entry and DNA Damage. Cancers 2019, 11, 1743.
  53. Weisberg, E.; Nonami, A.; Chen, Z.; Liu, F.; Zhang, J.; Sattler, M.; Nelson, E.; Cowens, K.; Christie, A.L.; Mitsiades, C.; et al. Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. Leukemia 2015, 29, 27–37.
More
Information
Subjects: Oncology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 387
Revisions: 2 times (View History)
Update Date: 03 Mar 2021
1000/1000