Abstract 4472: NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry: Comparison with NVP-BEZ235

BackgroundThe tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner.MethodsCT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting.ResultsThis study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread.ConclusionsThe in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.

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193 Phase I Safety Experience with the Oral Pan-class I PI3K Inhibitor BKM120 in Patients with Metastatic Breast Cancer (mBC)

European Journal of Cancer ◽

10.1016/s0959-8049(12)70261-7 ◽

2012 ◽

Vol 48 ◽

pp. S96

Author(s):

C. Saura ◽

H. Burris ◽

C.L. Arteaga ◽

I. Mayer ◽

C. Germa ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase I ◽

Metastatic Breast ◽

Pi3k Inhibitor ◽

Class I

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220 POSTER Combination of class I PI3K inhibitor, GDC-0941, with standard of care therapeutics results in enhanced anti-tumor responses in human cancer models in vitro and in vivo

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)72152-9 ◽

2008 ◽

Vol 6 (12) ◽

pp. 69-70 ◽

Cited By ~ 1

Author(s):

D. Sampath ◽

M. Belvin ◽

J. Guan ◽

K. Edgar ◽

J. Wallin ◽

...

Keyword(s):

Human Cancer ◽

Standard Of Care ◽

Pi3k Inhibitor ◽

Class I ◽

Cancer Models

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Abstract 980: AMG 511, a potent and selective class I PI3K inhibitor, suppresses the growth of Kras mutant lung tumors in mice

10.1158/1538-7445.am2012-980 ◽

2012 ◽

Author(s):

Juan Estrada ◽

Sharon Ungersma ◽

Stephen Kaufman ◽

Brittany Yerby ◽

Nancy Zhang ◽

...

Keyword(s):

Lung Tumors ◽

Pi3k Inhibitor ◽

Class I

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Abstract 2450: Either pan class I PI3K inhibitor or PI3K alpha selective inhibitor sensitizes head and neck squamous cell carcinoma cells to Erlotinib, an EGFR TKI.

10.1158/1538-7445.am2013-2450 ◽

2013 ◽

Cited By ~ 1

Author(s):

Ming Gao ◽

Yen-Shen Lu ◽

Li-Ping Hsiao ◽

Suz Wen Chen ◽

Ann-Lii Cheng

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Selective Inhibitor ◽

Carcinoma Cells ◽

Pi3k Inhibitor ◽

Neck Squamous Cell Carcinoma ◽

Class I ◽

Egfr Tki

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Abstract 2946: Role of EphB3 receptor in mediating head and neck tumor growth, cell migration, and response to PI3K inhibitor

10.1158/1538-7445.am2018-2946 ◽

2018 ◽

Author(s):

Shilpa Bhatia ◽

Anastacia Griego ◽

Shelby Lennon ◽

Ayman Oweida ◽

Jaspreet Sharma ◽

...

Keyword(s):

Cell Migration ◽

Tumor Growth ◽

Head And Neck ◽

Pi3k Inhibitor ◽

Head And Neck Tumor ◽

Neck Tumor

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Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer

Breast Cancer Research ◽

10.1186/s13058-020-01354-y ◽

2020 ◽

Vol 22 (1) ◽

Cited By ~ 1

Author(s):

Ana C. Garrido-Castro ◽

Cristina Saura ◽

Romualdo Barroso-Sousa ◽

Hao Guo ◽

Eva Ciruelos ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Clinical Benefit ◽

Triple Negative ◽

Pi3k Pathway ◽

Pi3k Inhibitor ◽

Class I ◽

Phase 2 ◽

Phase 2 Study ◽

Grade 3

Abstract Background Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. Methods This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. Results Fifty patients were enrolled. Median number of cycles was 2 (range 1–10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3). Median OS was 11.2 months (95% CI 6.2–25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. Conclusions Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. Trial registration NCT01790932. Registered on 13 February 2013; NCT01629615. Registered on 27 June 2012.

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Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models

Cancers ◽

10.3390/cancers12123857 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3857

Author(s):

Zhanfang Guo ◽

Tina Primeau ◽

Jingqin Luo ◽

Cynthia Zhang ◽

Hua Sun ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Triple Negative Breast Cancer ◽

Growth Response ◽

Triple Negative ◽

Pi3k Pathway ◽

Pi3k Inhibitor ◽

Pi3k Inhibitors ◽

Patient Derived Xenograft ◽

Phosphorylated Akt

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.

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