Continuous anti-angiogenic therapy after tumor progression in patients with recurrent high-grade epithelial ovarian cancer: phase I trial experience

Hou, Ming; Wang, Zhijie; Janků, Filip; Piha-Paul, Sarina A.; Naing, Aung; Hong, David S.; Westin, Shannon N.; Coleman, Robert L.; Sood, Anil K.; Tsimberidou, Apostolia M.; Subbiah, Vivek; Wheler, Jennifer J.; Zinner, Ralph; Lu, Karen H.; Meric‐Bernstam, Funda; Fu, Siqing

doi:10.18632/oncotarget.9048

Cited by 9 publications

(7 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Within the context of AURK inhibition in EOC, a large cohort of 240 patients with recurrent high-grade EOC who were referred to the phase I clinical trials program has been analyzed retrospectively [ 48 ]. Targeted agents included bevacizumab, vascular endothelial growth factor (VEGF) receptor inhibitors, and other compounds targeting the PI3K/AKT/mTOR, MAPK, Src, Wee1, and AURKA signaling pathways.…”

Section: Aurks In Ovarian Cancermentioning

confidence: 99%

Wise Management of Ovarian Cancer: On the Cutting Edge

Boussios

Mikropoulos

Samartzis

et al. 2020

JPM

View full text Add to dashboard Cite

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20–40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.

show abstract

Section: Aurks In Ovarian Cancermentioning

confidence: 99%

Wise Management of Ovarian Cancer: On the Cutting Edge

Boussios

Mikropoulos

Samartzis

et al. 2020

JPM

View full text Add to dashboard Cite

show abstract

“…TP53 plays many important roles in the prevention and suppression of abnormal cell growth through cell-cycle arrest, apoptosis, senescence, and DNA repair and induction of drug resistance [ 15 , 16 ]. Although the prognostic or predictive value of TP53 mutations has been inconclusive in NSCLC cases [ 17 – 23 ], recent studies demonstrated that antiangiogenic-based therapy may be appropriate for the treatment of TP53 -mutant NSCLC [ 24 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Outcome analysis of Phase I trial patients with metastaticKRASand/orTP53mutant non-small cell lung cancer

Wang

Piha-Paul

et al. 2018

Oncotarget

Self Cite

View full text Add to dashboard Cite

KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS+/TP53+, KRAS+/TP53-,KRAS-/TP53+, and KRAS-/TP53- NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS+/TP53+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.

show abstract

“…Blockade of downstream signaling pathways such as RAF/MEK or PI3K/AKT/mTOR in KRAS -mutant cancer [17] and antiangiogenic-based therapy in TP53 -mutant cancer would be appropriate therapeutic strategies [18, 19]. Unfortunately, effective therapies directly targeting TP53 or KRAS mutations are not available and these mutations are currently considered undruggable [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer

et al. 2017

Self Cite

View full text Add to dashboard Cite

PurposeGenetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+/TP53+ mutations.ResultsApproximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0.003). KRAS G13 and TP53 R273 mutations were associated with poor overall survival (OS), while antiangiogenesis and gene aberration-related therapies were associated with prolonged OS. A prognostic model using neutrophilia, thrombocytosis, hypoalbuminemia, body mass index <30 kg/m2, and the absence of lung metastasis was established and validated. Phase I cancer patients in the low-risk group had a median OS of 16.6 months compared with 5.4 months in the high-risk group (p < 0.001). Untreated patients in the low-risk group had a median OS of 6.7 months compared with 3.6 months in the high-risk group (p = 0.033).Experimental DesignWe analyzed 163 consecutive patients with advanced KRAS+/TP53+ mutant cancer who were referred to phase I clinical trials, to identify molecular aberrations, clinical characteristics, survivals, and potentially effective treatment regimens.ConclusionsThis study provided preliminary evidence that besides modulation of the proinflammatory state, antiangiogensis and concomitant gene aberration-related therapies may improve the treatment of KRAS+/TP53+ mutant cancer.

show abstract

Continuous anti-angiogenic therapy after tumor progression in patients with recurrent high-grade epithelial ovarian cancer: phase I trial experience

Cited by 9 publications

References 42 publications

Wise Management of Ovarian Cancer: On the Cutting Edge

Wise Management of Ovarian Cancer: On the Cutting Edge

Outcome analysis of Phase I trial patients with metastaticKRASand/orTP53mutant non-small cell lung cancer

Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer

Contact Info

Product

Resources

About