PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors

Abstract

Purpose: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression.Experimental Design: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo.Results: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1 R132H and 1p/19q codeletion) and PIK3CA E542K , and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/ AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo-evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma.Conclusions: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

“…This is in concordance with the general selection of aggressive tumors upon PDX generation in different tumor types, including pediatric brain tumors [ 13 ]. So far, only a handful of IDH1mut glioma models have been described, which all suffer from poor reproducibility, a long development time and/or changes in IDH1 status [ 55 , 69 , 75 , 99 , 106 , 109 ]. Successful IDH1mut models in our cohort were defined molecularly as high-grade astrocytomas with abundant chromosomal aberrations, CDKN2A/B loss, ATRX, and TP53 mutations and G-CIMP-low signature.…”

Tripartite motif‑containing 14 regulates cell proliferation and apoptosis in cervical cancer via the Akt signaling pathway

“…These findings fill the gap in the impact of TriM14 on cervical cancer. akt/mTor is a very important cell signaling pathway, which results in the occurrence and development of various tumors (13)(14)(15). The use of Akt/mTOR inhibitors can significantly inhibit or kill tumor cells (16).…”

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

“…This is in concordance with the general selection of aggressive tumors upon PDX generation in different tumor types, including pediatric brain tumors 73 . So far, only a handful of IDH1mut glioma models were described, which all suffer from long development time and/or changes in IDH1 status 67,[74][75][76][77][78] . Successful IDH1mut models in our cohort were defined molecularly as high-grade astrocytomas with abundant chromosomal aberrations, CDKN2A/B loss, ATRX and TP53 mutations and G-CIMP-low signature.…”