Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuro-Oncology
Published in: Journal of Neuro-Oncology 1/2014

01-03-2014 | Topic Review

PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer

Authors: Parvin F. Peddi, Sara A. Hurvitz

Published in: Journal of Neuro-Oncology | Issue 1/2014

Login to get access

Abstract

The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood–blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs.
Literature
1.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRef
2.
Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRef
3.
Baselga J, Cortes J, Kim SB et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119PubMedCrossRef
4.
Verma S, Miles D, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791PubMedCrossRef
5.
Brufsky AM, Mayer M, Rugo HS et al (2011) Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834–4843PubMedCrossRef
6.
Souglakos J, Vamvakas L, Apostolaki S et al (2006) Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status. Breast Cancer Res 8:R36PubMedCentralPubMedCrossRef
7.
Leyland-Jones B (2009) Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol 27:5278–5286PubMedCrossRef
8.
9.
10.
Bendell JC, Domchek SM, Burstein HJ et al (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972–2977PubMedCrossRef
11.
Palmieri D, Bronder JL, Herring JM et al (2007) Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67:4190–4198PubMedCrossRef
12.
Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V (2007) Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood–brain barrier. Anticancer Drugs 18:23–28PubMedCrossRef
13.
Laufman LR, Forsthoefel KF (2001) Use of intrathecal trastuzumab in a patient with carcinomatous meningitis. Clin Breast Cancer 2:235PubMedCrossRef
14.
Oliveira M, Braga S, Passos-Coelho JL, Fonseca R, Oliveira J (2011) Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab. Breast Cancer Res Treat 127:841–844PubMedCrossRef
15.
Platini C, Long J, Walter S (2006) Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 7:778–780PubMedCrossRef
16.
Mir O, Ropert S, Alexandre J, Lemare F, Goldwasser F (2008) High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer. Ann Oncol 19:1978–1980PubMedCrossRef
17.
Taskar KS, Rudraraju V, Mittapalli RK et al (2012) Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res 29:770–781PubMedCentralPubMedCrossRef
18.
Gril B, Palmieri D, Bronder JL et al (2008) Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100:1092–1103PubMedCrossRef
19.
Cameron D, Casey M, Press M et al (2008) A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543PubMedCrossRef
20.
Lin NU, Dieras V, Paul D et al (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459PubMedCrossRef
21.
Bachelot T, Romieu G, Campone M et al (2013) Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 14:64–71PubMedCrossRef
22.
23.
Baselga J (2011) Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 16(suppl 1):12–19PubMedCrossRef
24.
Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28:1075–1083PubMedCrossRef
25.
Gewinner C, Wang ZC, Richardson A et al (2009) Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16:115–125PubMedCentralPubMedCrossRef
26.
Dibble CC, Asara JM, Manning BD (2009) Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 29:5657–5670PubMedCentralPubMedCrossRef
27.
O’Reilly KE, Rojo F, She QB et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates AKT. Cancer Res 66:1500–1508PubMedCentralPubMedCrossRef
28.
Lopez-Knowles E, O’Toole SA, McNeil CM et al (2010) PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer 126:1121–1131PubMed
29.
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70CrossRef
30.
Berns K, Horlings HM, Hennessy BT et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402PubMedCrossRef
31.
Jegg AM, Ward TM, Iorns E et al (2012) PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells. Breast Cancer Res Treat 136:683–692PubMedCrossRef
32.
33.
Hohensee I, Lamszus K, Riethdorf S et al (2013) Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases. Am J Pathol 183:83–95PubMedCrossRef
34.
O’Reilly T, McSheehy PM, Kawai R et al (2010) Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents. Cancer Chemother Pharmacol 65:625–639PubMedCrossRef
35.
Franz DN, Belousova E, Sparagana S et al (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381:125–132PubMedCrossRef
36.
Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529PubMedCrossRef
37.
Andre F, Campone M, O’Regan R et al (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110–5115PubMedCrossRef
38.
Morrow PK, Wulf GM, Ensor J et al (2011) Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 29:3126–3132PubMedCrossRef
39.
O’Regan R, Ozguroglu M, Andre F et al (2013) Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). J Clin Oncol 31 (suppl; abstr 505)
40.
Zhao H, Cui K, Nie F et al (2012) The effect of mTOR inhibition alone or combined with MEK inhibitors on brain metastasis: an in vivo analysis in triple-negative breast cancer models. Breast Cancer Res Treat 131:425–436PubMedCrossRef
41.
Wolff AC, Lazar AA, Bondarenko I et al (2013) Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 31:195–202PubMedCrossRef
42.
Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304PubMedCrossRef
43.
Lin F, Buil L, Sherris D, Beijnen JH, van Tellingen O (2013) Dual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2. Int J Cancer 133(5):1222–1233PubMedCrossRef
44.
Carracedo A, Ma L, Teruya-Feldstein J et al (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3 K-dependent feedback loop in human cancer. J Clin Invest 118:3065–3074PubMedCentralPubMed
45.
Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC et al (2011) mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov 1:248–259PubMedCentralPubMedCrossRef
46.
Maira SM, Pecchi S, Huang A et al (2012) Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-Kinase inhibitor. Mol Cancer Ther 11:317–328PubMedCrossRef
47.
Nanni P, Nicoletti G, Palladini A et al (2012) Multiorgan Metastasis of Human HER-2(+) Breast Cancer in Rag2(-/-);Il2rg(-/-) Mice and Treatment with PI3K Inhibitor. PLoS One 7:e39626PubMedCentralPubMedCrossRef
48.
Maira M, Schnell C, Lollini P et al (2012) Preclinical and preliminary clinical activity of NVP-BKM120, an oral pan-class I PI3K inhibitor, in the brain. Ann Oncol 23 (suppl 9; abstr 1675)
49.
Wen P, Yung W, Mellinghoff I et al (2013) Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM). J Clin Oncol 31 (suppl; abstr 2015)
50.
Bendell JC, Rodon J, Burris HA et al (2012) Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 30:282–290PubMedCrossRef
51.
Pistilli B, Urruticoechea A, Chan S et al (2012) Ph Ib/II study of BKM120 plus trastuzumab (T) in patients with T-resistant HER2+ advanced breast cancer (BC). Ann Oncol 23 (suppl 9; abstr 3180)
52.
Tohda C, Nakanishi R, Kadowaki M (2009) Hyperactivity, memory deficit and anxiety-related behaviors in mice lacking the p85alpha subunit of phosphoinositide-3 kinase. Brain Dev 31:69–74PubMedCrossRef
53.
Ackermann TF, Hortnagl H, Wolfer DP et al (2008) Phosphatidylinositide dependent kinase deficiency increases anxiety and decreases GABA and serotonin abundance in the amygdala. Cell Physiol Biochem 22:735–744PubMedCrossRef
54.
Koul D, Shen R, Kim YW et al (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12:559–569PubMedCentralPubMedCrossRef
55.
Hong DS, Bowles DW, Falchook GS et al (2012) A multicenter Phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 18:4173–4182PubMedCrossRef
56.
Edelman G, Bedell C, Shapiro G (2010) A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies. J Clin Oncol 28(6):1075–1083 (suppl; abstr 3004)CrossRef
57.
Cloughesy TF, Mischel P, Omuro A et al (2013) Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study. J Clin Oncol 31 (suppl; abstr 2012)
58.
Liu TJ, Koul D, LaFortune T et al (2009) NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 8:2204–2210PubMedCentralPubMedCrossRef
59.
Krop I, Saura C, Rodon J et al (2012) A Phase I/Ib dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer. J Clin Oncol 30(12):282–290 suppl; abstr 508
60.
Brana I, LoRusso P, Baselga J et al (2010) A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies. J Clin Oncol 28 (suppl; abstr 3030)
61.
Salphati L, Heffron TP, Alicke B et al (2012) Targeting the PI3K pathway in the brain-efficacy of a pi3k inhibitor optimized to cross the blood–brain barrier. Clin Cancer Res 18:6239–6248PubMedCrossRef
62.
Peddi PF, Hurvitz SA (2014) What Does the Future Hold for PI3K/AKT/mTOR Inhibitors in BreastCancer? J OncoPathol 1(4):73-81
Metadata
Title
PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer
Authors
Parvin F. Peddi
Sara A. Hurvitz
Publication date
01-03-2014
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 1/2014
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-014-1369-6

Other articles of this Issue 1/2014

Journal of Neuro-Oncology 1/2014 Go to the issue

Clinical Study

A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas

Letter to the Editor

The Neutrophil Lymphocyte Ratio in Patients with Glioblastoma Multiforme

Clinical Study

CSF CA 15-3 in breast cancer-related leptomeningeal metastases

Clinical Study

Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme

Laboratory Investigation

C-terminally truncated form of αB-crystallin is associated with IDH1 R132H mutation in anaplastic astrocytoma

Clinical Study

Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma