A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer

Moore, Kathleen N.; Hong, David S.; Patel, Manish R.; Pant, Shubham; Ulahannan, Susanna; Jones, Suzanne F.; Meric‐Bernstam, Funda; Wang, Judy S.; Aljumaily, Raid; Hamilton, Erika; Wittchen, Erika S.; Wang, Xuejing; Lin, Aimee Bence; Bendell, Johanna C.

doi:10.1007/s11523-021-00835-0

Cited by 16 publications

(7 citation statements)

References 35 publications

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“…These data suggest that the inhibition of ATM/ATR/Chk1/Wee1 may offer a therapeutic strategy in OC independently from the HR-proficient/deficient background both as single agents and in combination with a platinum drug. Phase I studies of the combination of platinum compounds and inhibitors of ATR [ 41 , 42 , 43 ], Wee1 [ 44 ] and Chk1 [ 45 , 46 ] in solid tumors are already available, and further clinical investigations are warranted with schedule refinement to help manage toxicity. Interestingly, the combination of ATR/Wee1 inhibitors was also synergic in both sensitive and resistant F3 and Brca1−/− cells.…”

Section: Discussionmentioning

confidence: 99%

Different Patterns of Platinum Resistance in Ovarian Cancer Cells with Homologous Recombination Proficient and Deficient Background

Chiappa,

Guffanti,

Grasselli

et al. 2024

IJMS

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Platinum compounds are very active in first-line treatments of ovarian carcinoma. In fact, high rates of complete remission are achieved, but most patients eventually relapse with resistant disease. Many mechanisms underlying the platinum-resistant phenotype have been reported. However, there are no data in the same isogenic cell system proficient and deficient in homologous recombination (HR) on platinum-acquired resistance that might unequivocally clarify the most important mechanism associated with resistance. We generated and characterized cisplatin (DDP)-resistant murine ovarian ID8 cell lines in a HR-deficient and -proficient background. Specific upregulation of the NER pathway in the HR-proficient and -resistant cells and partial restoration of HR in Brca1−/−-resistant cells were found. Combinations of different inhibitors of the DNA damage response pathways with cisplatin were strongly active in both resistant and parental cells. The data from the ID8 isogenic system are in line with current experimental and clinical evidence and strongly suggest that platinum resistance develops in different ways depending on the cell DNA repair status (i.e., HR-proficient or HR-deficient), and the upregulation and/or restoration of repair pathways are major determinants of DDP resistance.

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Section: Discussionmentioning

confidence: 99%

Different Patterns of Platinum Resistance in Ovarian Cancer Cells with Homologous Recombination Proficient and Deficient Background

Chiappa,

Guffanti,

Grasselli

et al. 2024

IJMS

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“…Hematologic toxicity was the most frequent AE and was dose limiting. The ORR was 4.9% and 12.5% in combination with cetuximab and 5-fluorouracil, respectively [ 112 ].…”

Section: Targeted Drug Modulation Of Stemness Pathwaysmentioning

confidence: 99%

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer

Martínez-Pérez,

Torrado,

Domínguez-Cejudo

et al. 2024

IJMS

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The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/β-catenin, Hedgehog, Notch, TGF-β/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.

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“…Failure of immunotherapy is frequently caused by autoimmune diseases. A list of clinical trials on Rictor inhibitors in gastrointestinal cancer is provided in Table II (132)(133)(134)(135)(136). At present, second-generation mTOR inhibitors include dual mTOR/PI3K inhibitors, such as PI-103, NVP-BEZ235 and WJD008; selective mTORC1/2 inhibitors, such as Torin1, PP242 and PP30, and others, such as Ku -0063794, WAY-600, WYE-687 and WYE354, which have been reported to be ATP-competitive mTOR inhibitors, as they effectively inhibit mTORC1 and mTORC2 (137).…”

Section: Targeted Therapymentioning

confidence: 99%

Roles of Rictor alterations in gastrointestinal tumors (Review)

Cao,

Guo,

Min

et al. 2024

Oncol Rep

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Gastrointestinal tumors account for five of the top 10 causes of mortality from all cancers (colorectal, liver, stomach, esophageal and pancreatic cancer). Mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in various human cancers. As a core component of the mTOR complex 2 (mTORC2), Rictor is a key effector molecule of the PI3K/Akt pathway. A high alteration rate of Rictor has been observed in gastrointestinal tumors, and such Rictor alterations are often associated with resistance to chemotherapy and related adverse clinical outcomes. However, the exact roles of Rictor in gastrointestinal tumors remain elusive. The aim of the present study was to critically discuss the following: i) Mutation and biological characteristics of Rictor in tumors with a detailed overview of Rictor in cell proliferation, angiogenesis, apoptosis, autophagy and drug resistance; ii) the role of Rictor in tumors of the digestive system, particularly colorectal, hepatobiliary, gastric, esophageal and pancreatic cancer and cholangiocarcinoma; and iii) the current status and prospects of targeted therapy for Rictor by inhibiting Akt activation. Despite the growing realization of the importance of Rictor/mTORC2 in cancer, the underlying mechanistic details remain poorly understood; this needs to change in order for the development of efficient targeted therapies and re-sensitization of therapy-resistant cancers to be made possible.

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A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer

Cited by 16 publications

References 35 publications

Different Patterns of Platinum Resistance in Ovarian Cancer Cells with Homologous Recombination Proficient and Deficient Background

Different Patterns of Platinum Resistance in Ovarian Cancer Cells with Homologous Recombination Proficient and Deficient Background

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer

Roles of Rictor alterations in gastrointestinal tumors (Review)

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