Predicting tumour response to anti-HER1 therapy using medical imaging: a literature review andin vitrostudy of [¹⁸F]-FDG incorporation by breast cancer cells responding to cetuximab

Abstract

Cetuximab, an anti-HER1 (EGFR) antibody, is currently under trial for the treatment of breast cancer. HER1 expression is not necessarily a predictor of response to cetuximab as mutant components of the pathways activated by HER1 which include PI3K/Akt can lead to resistance. Techniques that monitor events downstream of HER1 are more likely to provide an accurate measure of the efficacy of an anti-HER1 treatment. Glucose metabolism has been shown to be strongly influenced by the state of activation of PI3K/Akt. Here, the association between [18F]-FDG incorporation in breast cancer cells during response to cetuximab is investigated. The study also reviews the development of medical imaging probes that target HER1 The sensitivity to cetuximab of three breast tumour cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing HER1 at low and high levels, are determined using an MTT assay over a six-day period and a clonogenic assay carried out after seven- and 10-day exposures. Incorporation of FDG by cells treated with growth inhibitory doses of cetuximab were carried out after 4 hand two, four and six days of treatment. Glucose transport (rate of uptake of the non-metabolisable analogue [3H]o-methyl-D-glucose), hexokinase activity and lactate production were measured on cells treated with inhibitory doses of cetuximab for six days. The IC50, dose for MDA-MB-468 cells and the IC10 (maximum achievable inhibition) doses for MDA-MB-543 and SKBr3 treated with cetuximab for six days were 2.6, 5 and 148 microg/mL, respectively. Incorporation of FDG by SKBr3 and MDA-MB-453 cells was found to be decreased by MDA-MB468 cells using IC50, and IC20, doses of cetuximab for six days. Lactate production was found to be increased by MDA-MB-468 cells responding to cetuximab. Incorporation of FDG at the tumour cell level is modulated by treatment with growth inhibitory doses of cetuximab in cells sensitive to cetuximab due to modulation of HK activity.

Early FDG/PET Scanning as a Pharmacodynamic Marker of Anti-EGFR Antibody Activity in Colorectal Cancer

“…Studies of patients with absent or low tumor EGFR expression by immunohistochemistry have found that response rates are statistically indistinguishable from those patients with higher EGFR expression, indicating that immunohistochemical staining may not always detect physiologically relevant receptor expression (2,3). An important consequence of EGFR activation is increased glucose uptake and retention, which supports tumor energetic and biosynthetic requirements (4,5,6), suggesting that 18 F-fluorodeoxyglucosepositron emission tomography (FDG-PET) may be a sensitive assay for detection of changes in EGFR activity (7,8). Here, we describe a chemotherapy-refractory patient whose tumor was negative for EGFR expression by immunohistochemistry in whom we used FDG-PET to show a panitumumab-mediated decrease in FDG accumulation over a period of 48 hours, leading to a progressive decline in metabolic activity and partial response by Response Evaluation Criteria in Solid Tumors (RECIST; ref.…”

A cleavable peptide adapter augments the activity of targeted toxins in combination with the glycosidic endosomal escape enhancer SO1861

“…Using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays, cytotoxicity of DE and DAES with or without SO1861 (125 ng/mL) was determined on the EGFR-positive colon cancer cell line HCT 116 and the mammary gland carcinoma cell line MDA-MB-453, which expresses only low amounts of EGFR [ 25 , 26 ] (see also Additional file 6 ).…”

“…Here, HCT 116 cells were cultured in McCoy’s medium (Gibco, Thermo Fisher Scientific, Waltham, MA, USA). MDA-MB-453 cells (ATCC, Manassas, VA, USA) in contrast express low amounts of EGFR [ 25 , 26 ]. This cell line has been isolated from the metastatic site of a patient with mammary gland carcinoma [ 40 ].…”

Early decline in serum phospho-CSE1L levels in vemurafenib/sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts

“…However, false-positive or equivocal results are a known limitation of FDG-PET/CT in cancer evaluation [41]. The metabolism of glucose is mediated by Akt (v-Akt murine thymoma viral oncogene)/PKB (protein kinase-B) pathway, and Akt is regulated by EGFR-PI3K (phosphatidylinositol-3-kinase) signaling [42]. Accordingly, it should not be assumed that FDG-PET/CT can be used for assaying the therapeutic response of all molecular-targeted therapies.…”