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Serial Multi-omics Uncovers Anti-Glioblastoma Responses Not Evident by Routine Clinical Analyses (Phosphoproteomics)

ABSTRACT: Recurrent glioblastoma (rGBM) is incurable. Serial “multi-omic” assays from longitudinal rGBM biopsies may unravel tumor responses to a treatment. Despite traditional imaging indicating tumor progression, 86 serial rGBM biopsies cores obtained over 4 months from the first two patients on a clinical trial of repeated intratumoral doses of the immunotherapeutic agent, CAN-3110, revealed therapeutic effects by multi-omic analyses, including: a-longitudinal and spatial reshaping of the rGBM’s microenvironment, b- expansion of new T cell tissue-resident effector memory clonotypes against newly characterized CAN-3110 epitopes and other undetermined antigens, and c-novel expression of HLA-immunopeptides including cancer testes antigens. The two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand GBM’s evolution during an investigational therapy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Break Through Cancer

LAB HEAD: Dr. Forest M. White

PROVIDER: PXD063976 | Pride | 2025-10-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Global_phosphoproteome.csv	Csv
	Pateint1_pTyr_search.mzML	Mzml
	Patient1_IP_Supernatant.raw	Raw
	Patient1_Phos_F.mzData	Other
	Patient1_Phos_F1.raw	Raw

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Project description:Mitogen activated protein kinase kinase kinase 1 (MAP3K1), is involved in various cancer signaling networks including the NF-B, JNK, ERK, and p38 pathways. Functioning as a signaling kinase in these oncogenic pathways, MAP3K1 contributes to tumor growth and metastasis. Additionally, higher transcript levels of MAP3K1 in pancreatic patient tumors is associated with poorer 5-year survival, suggesting MAP3K1 is an attractive therapeutic target. Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKK), an important phosphorylation target of MAP3K1, was shown to be important in pancreatic cancer (PC) disease onset and progression. We previously reported a quinoxaline analog, Analog 84, which inhibits IKK phosphorylation and downstream NF-B pathway activation. To improve the metabolic stability and bioavailability of Analog 84, we developed 51-106, which moved -F atom to block a site of potential metabolism. Using a chemoproteomics approach for kinome profiling, KiNativTM, we show 51-106 selectively binds to MAP3K1 in an ATP-competitive manner. Follow up studies show 51-106 inhibits downstream phosphorylation of IKK and blocks TNF-induced MAP3K1-IKK-mediated NF-B activity. Treatment of PC cell lines MiaPaCa2 and PANC-1 with 51-106 inhibits cell growth and migration with low micromolar potency. Utilizing 51-106 as a tool to study MAP3K1 signaling, we use phosphoproteomics analysis to show MAP3K1 inhibition leads to a dose dependent decrease in NPM1 T199 phosphorylation, suggesting NPM1 may play a role in MAP3K1 signaling. We observe a dose-dependent S-phase arrest in cells treated with 51-106, potentially linking MAP3K1 inhibition to a dysfunctional DNA damage response. Consistent with this observation, in combination studies, 51-106 synergistically inhibited growth with gemcitabine in LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) cell lines in vitro and in KPC syngeneic orthotopic implantation mouse model of pancreatic cancer in vivo. Our data indicated that MAP3K1 inhibition may represent a promising therapeutic in PC. These findings underscore the need for further investigation into the molecular interactions and downstream effects of the MAP3K1-NPM1 signaling axis.

Dataset Information

Serial Multi-omics Uncovers Anti-Glioblastoma Responses Not Evident by Routine Clinical Analyses (Phosphoproteomics)

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