LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer
Abstract
:1. Introduction
2. LKB1 and Tumor Metabolism
2.1. Inhibition of Anabolic Pathways
2.2. Activation of Catabolic Pathways
3. LKB1 and Angiogenesis
4. LKB1 and Response to Non-Immunotherapy Treatments
4.1. Platinum-Based Chemotherapy
4.2. Anti-Angiogenic Treatment
4.3. Other Non-Chemotherapy Agents
5. LKB1 and Immunotherapy
5.1. LKB1 and Immune Microenvironment
5.2. LKB1 and Response to Immunotherapy
6. The Interplay between Immune and Angiogenic Microenvironment
7. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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A. Clinical Trials Requiring STK11/LKB1 Determination as Inclusion Criteria | ||||
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Clinical Trial ID | Phase | Brief Description | Study Population | Primary Endpoint |
NCT03709147 (FAME trial) | II | Exploiting metformin plus/minus cyclic fasting mimicking diet (FMD) to improve the efficacy of platinum-pemetrexed chemotherapy in advanced LKB1-inactive lung adenocarcinoma | LKB1 inactive advanced NSCLC | PFS |
NCT03872427 (BeGIN trial) | II | A phase II Basket trial of Glutaminase Inhibitor (BeGIN) CB-839 HCl in patients with NF1 aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 aberrant tumors. | NF1 aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 aberrant tumors | ORR |
NCT03375307 | II | A phase II study of Olaparib (AZD2281) in patients with metastatic/advanced urothelial carcinoma with DNA-repair defects. | Metastatic/advanced urothelial carcinoma with DNA-repair defects (among these: STK11 gene mutations). | ORR |
NCT02352844 | II | A Phase II Study of Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 mutations. | Advanced solid malignancies with TSC1, TSC2, NF1, NF2, or STK11 mutations. | ORR |
NCT02645149 | IV | Molecular profiling and matched targeted therapy for patients with metastatic melanoma. Once standard therapies have been exhausted, patients receive a targeted therapy matched for their genetic result, if applicable. If STK11 mutated, they receive everolimus. | BRAF and NRAS wild-type unresectable Stage III or Stage IV metastatic melanoma. | Type and frequency of genetic aberrations in BRAF/NRAS wild-type metastatic melanoma and proportion of patients with BRAS/NRAS wild-type melanoma receiving targeted therapy |
B. Clinical Trials Investigating STK11/LKB1 Status Among Secondary Objectives | ||||
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Clinical Trial ID | Phase | Brief Description | Study Population | Primary Endpoint |
NCT01470209 | I | A phase I study assessing the safety of the combination of everolimus and BKM120 for the treatment of advanced solid tumors cancer in patients who are no longer benefiting from or unable to withstand standard treatment. | Solid tumors (including lung cancer). Alterations in PIK3CA, NF1, TSC1/TSC2, mTOR, KRAS, LKB1, PTEN will be accessed. | DLT |
NCT02642042 | II | A phase II Trial of Trametinib with docetaxel in Non-Small Cell Lung Cancer (NSCLC) KRAS mutated patients after one or two prior systemic therapies. | Advanced NSCLC carrying KRAS mutation Tertiary objective: To evaluate the response rate in the presence of co-mutations TP53 and LKB1 | ORR |
NCT01310231 | II | A randomized phase II, double blind trial of standard chemotherapy with metformin (versus placebo) in women with metastatic breast cancer receiving first, second, third or fourth line chemotherapy with anthracycline, taxane, platinum, capecitabine or vinorelbine based regimens. | Metastatic breast cancer in first, second, third or fourth line chemotherapy treatment. Immunohistochemistry analysis of different markers (IR, LKB1, phosphorylated AKT, S6K, ribosomal protein S6, 4E-BP1, and stathmin) performed. | PFS |
NCT02285855 | II | Tumor mutation status and metabolic response to metformin in non-small cell lung cancer (NSCLC). | NSCLC undergoing Stereotactic body Radiotherapy (SBRT). Genotype comparisons of JKRAS, STK11, and TP53 mutations assessed. | ORR [Closed for poor accrual] |
NCT03495544 | Observational | Comparative multicenter study estimating association between germline DNA-repair genes mutations and PD-L1 expression level in breast cancer. | Breast cancer. Association between germline mutations (TP53 MLH1 MSH2 MSH6 PMS2 EPCAM APC MUTYH CDKN2A CDK4 ATM KIT PDGFRA CDH1 CTNNA1 PRSS1 SPINK1 BRCA1 BRCA2 FANCI FANCL PALB2 RAD51B RAD51C RAD54L RAD51D CHEK1 CHEK2 CDK12 BRIP1 PPP2R2A BARD1 PARP1 STK11 XRCC3) and PD-L1 expression. | Diagnostic performance of PD-L1 expression in breast cancer |
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Bonanno, L.; Zulato, E.; Pavan, A.; Attili, I.; Pasello, G.; Conte, P.; Indraccolo, S. LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer. Int. J. Mol. Sci. 2019, 20, 1874. https://doi.org/10.3390/ijms20081874
Bonanno L, Zulato E, Pavan A, Attili I, Pasello G, Conte P, Indraccolo S. LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer. International Journal of Molecular Sciences. 2019; 20(8):1874. https://doi.org/10.3390/ijms20081874
Chicago/Turabian StyleBonanno, Laura, Elisabetta Zulato, Alberto Pavan, Ilaria Attili, Giulia Pasello, PierFranco Conte, and Stefano Indraccolo. 2019. "LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer" International Journal of Molecular Sciences 20, no. 8: 1874. https://doi.org/10.3390/ijms20081874