An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery—the BUMPER study

Amaral, Teresa; Niessner, Heike; Sinnberg, Tobias; Thomas, Ioannis; Meiwes, Andreas; Garbe, Claus; Garzarolli, Marlene; Rauschenberg, Ricarda; Eigentler, Thomas; Meier, Friedegund

doi:10.1093/noajnl/vdaa140

Cited by 15 publications

(18 citation statements)

References 43 publications

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“…The strong effects of the low preventive dose were confirmed using the second H1 melanoma model ( Supplementary Figure 5 ). In contrast to the findings with the preventive schedules, treating established metastasis with 12.5 mg/kg/d GNE-317 led only to moderate effects on the growth of established BMs ( Figure 5C-E ), which is in line with the lack of response of established BM when MM patients were treated with the PI3K inhibitor buparlisib 14 . These data imply that there is a substantial benefit of starting low-dose drug administration with GNE-317 during the earliest steps of brain colonization.…”

Section: Resultsmentioning

confidence: 47%

“…These established human BM showed PAM pathway activation in many cases, but activation patterns were quite heterogenous ( Figure 3B ). Together with the biosensor study and in light of a clinical trial showing insufficient response to a PI3K inhibitor in MM patients with established BM 14 , this provided a clear rationale to experimentally test the BM-suppressive effects of GNE-317 in various schedules. Here, we hypothesize that the PAM pathway inhibitor has the strongest effects on early, fate-deciding steps of BM formation where the PAM pathway could play the most relevant and consistent role.…”

Section: Resultsmentioning

confidence: 99%

“…Activation of PAM pathway in tumors of many entities is associated with cell proliferation, disease progression, angiogenesis, treatment resistance, and invasion 10 . Therapeutic treatment with single or dual PI3K/mTOR inhibitors has previously shown to reduce the growth of established BM in preclinical studies 11 – 13 , but failed to lead to intracranial response in MM patients with established BM in a clinical trial 14 .…”

Section: Introductionmentioning

confidence: 99%

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The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

et al. 2021

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Background Brain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions. Methods To investigate the temporo-spatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice. Results In vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation - permanent intravascular arrest, extravasation, and initial perivascular growth - are most vulnerable to dual PI3K/mTOR inhibition. Conclusion These findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.

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Section: Resultsmentioning

confidence: 47%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

et al. 2021

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“…A separate trial (BUMPER) evaluating the CNSpenetrable pan-PI3K inhibitor buparlisib in untreated MBM demonstrated that buparlisib monotherapy produced no intracranial responses in MBM patients unselected for PI3K pathway activation, although the drug itself was well tolerated (112). The MEK inhibitor binimetinib showed modest efficacy in a pilot study of 11 patients with NRAS mutated MBM who had failed multiple previous lines of therapy (113).…”

Section: All Authorsmentioning

confidence: 99%

The role of systemic therapy in melanoma brain metastases: a narrative review

Saleem¹,

Davar²

2022

Chin Clin Oncol

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Background and Objective: Melanoma is a disease notorious for the development of brain metastases, with consequently poor outcomes for patients who develop melanoma brain metastases (MBM). The treatment options for patients with MBM were limited to radiotherapy and surgery. MBM patients, particularly those with symptomatic disease, were excluded from clinical trials of immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors. Recent post-approval studies have, demonstrated important roles for existing systemic ICIs and BRAF/MEK inhibitors in untreated MBM, dramatically altering the landscape of melanoma patients in general and MBM in particular. These trials have also identified key areas for which more effective strategies are needed including: symptomatic MBM, and leptomeningeal disease (LMD).Methods: PubMed, Scopus and Embase databases were systematically queried to obtain records pertaining to the etiology of and treatment for MBM. Clinical trial databases were reviewed to obtain details regarding MBM clinical trials.

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“…Regarding specific therapeutics, we used drugs to inhibit the MAPK and BCL-2 family members. AKT was inhibited with siRNA, although there are a number of drugs blocking PI3K/AKT that are being tested in clinical trials for melanoma [57][58][59].…”

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confidence: 99%

CD133 Promotes Resistance to Trametinib in Melanoma Stem Cells by Activating an AKT / BCL-2 Survival Pathway

Cm¹,

Haribabu²,

Vakili³

et al. 2021

Preprint

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Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC), implicated in tumorigenesis, invasion, and drug resistance, and characterized by elevated expression of stem cell markers, such as CD133. We previously showed that siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. The current study investigates underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockdown or Dox-inducible expression of CD133. To maintain stable expression of CD133, MACS-sorted CD133(+) positive cells were expanded by ROCK-mediated conditional reprogramming of BAKP melanoma cells (BAKR). BAKR showed increased survival via reduced apoptosis after exposure to trametinib or DTIC, compared to BAKP. CRISPR-Cas9- mediated CD133 knockdown in BAKR cells (BAKR-T3) re-sensitized the cells, while CRISPR-Cas9 knockdown of CD133 in parental BAKP and POT cells even further increased trametinib-induced apoptosis (cleaved PARP) by reducing levels of anti-apoptotic BCL-xL, p-AKT, and p-BAD, and increasing pro-apoptotic BAD and active BAX. Dox-induced CD133 overexpression had the opposite effect, and blocked trametinib-induced apoptosis in both cell lines, coincident with elevated p-AKT, p-BAD, BCL-2 and BCL-xL and decreased levels of the active form of BAX and caspases-3 and -9. The roles of CD133 in AKT and BAD phosphorylation, or in the upregulation of anti-apoptotic BCL-2 family members, was further investigated by AKT knockout with siRNA, or inhibition of BCL-2 family members with navitoclax (ABT-263). Similar to CD133 knockdown, AKT1/2 siRNA knockdown in BAKP cells also reduced p-BAD. CD133 knockdown (T3)-mediated reduction of pBAD levels was equivalent in AKT-knockdown or AKT control cells indicating that CD133 may be upstream of AKT signaling. In BAKP cells treated with trametinib and/or ABT-263, effects of ABT-263 mirrored CD133 knockdown, since levels of active BAX and cleaved-PARP in BAKP-SC (CD133-) cells increased to the same level as that exhibited by BAKP-T3 cells (CD133+). CD133 may therefore activate a survival pathway where 1) increased phosphorylation of AKT induces 2) phosphorylation and inactivation of BAD, 3) decrease in the active form of BAX, and 4) reduction in caspase-mediated PARP cleavage, indicating apoptosis suppression leading to drug resistance in melanomas. Targeting survival pathways by which CD133 may confer chemoresistance in MICs can contribute to development of more effective treatments for patients with high-risk melanoma.

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An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery—the BUMPER study

Cited by 15 publications

References 43 publications

The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

The role of systemic therapy in melanoma brain metastases: a narrative review

CD133 Promotes Resistance to Trametinib in Melanoma Stem Cells by Activating an AKT / BCL-2 Survival Pathway

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