What's stopping EGFR inhibitors from being more effective?

Response rates with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in cancer treatment have been low. However, a recent study may have shed some light by revealing a kinase-independent function of EGFR in maintaining cell survival.

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Using prostate, breast and colon cancer cells, it was demonstrated that small interfering RNA (siRNA)-mediated knockdown of EGFR, but not inhibition of EGFR kinase activity, leads to autophagic cell death. Autophagy can occur when external energy sources are low or unobtainable and, although glucose levels remained constant in cells treated with kinase inhibitors, they were decreased by around 50% in cells transfected with EGFR siRNA.

The study found that EGFR–SGLT1 may confer a survival advantage to cancer cells by maintaining a basal level of intracellular glucose and preventing autophagy. This may help to explain previous data indicating that inhibition of EGFR kinase activity is not sufficient to induce cell death, or to negate all of the functions of EGFR.

Targeting both kinase-dependent and kinase-independent functions of EGFR may be necessary for more successful therapy in the future.

Source:

Cancer Cell (free download)

New promise for brain cancer patients with glioblastoma multiforme

Image via WikipediaGlioblastoma multiforme patients could live a year longer by taking the new experimental CDX-110 vaccine from Avant Immunotherapeutics and Pfizer, according to two small Phase II studies presented at the American Society of Clinical Oncology meeting recently.

The vaccine targets the tumour-specific molecule EGFR variant III, which is linked with poor prognosis.

Used with the standard chemotherapy treatment, temozolomide, the vaccine extended the length of life and was also mostly well-tolerated in the Phase II ACTIVATE trial of 21 brain cancer patients and the ongoing ACT II study of 23 patients.

Exclusive global rights to the vaccine were picked up by Pfizer of New York, from Avant Immunotherapeutics of Needham, Mass. in April.

GBM is the most common kind of brain tumour and is very aggressive. Average survival is 13 months to 15 months, with about half of patients dying within that timeframe and a few living two to three years. Those with tumors that express EGFRvIII are extremely unlikely to survive past two years. CDX-110 teaches the immune system to attack EGFRvIII on the tumor.

In the ACTIVATE trial, researchers looked at 21 patients with newly-diagnosed EGFRvIII-expressing GBM who had surgical resection and radiation therapy with oral temozolomide, the standard chemotherapy treatment, and did not have tumor progression. Sixteen patients had three doses of the vaccine at two-week intervals with granulocyte-macrophage colony stimulating factor, while the other five initially had placebo and were later given the vaccine.

Patients who received the vaccine had a median survival of 26 months versus 15.2 months for a matched historical cohort, while median-time-to-progression was 14.2 months compared to 7.13 months. No significant adverse events were reported.

In the similarly designed ACT trial of 23 patients, overall survival with the vaccine was estimated at 33.1 months versus 14.3 months for the matched historical cohort, while time-to-progression was 16.6 months, compared to 6.4 months.

Side effects appeared to be mild and tolerable; some patients experienced redness and itchiness at the injection site, but the side effects did not cause them to discontinue treatment. There were also some mild allergic reactions.

The Phase IIb/III trial was designed to include 90 and then 375 patients and began accruing nine months ago, with enrollment due to complete by year's end and data set for release in 2009. Avant's recently-forged partnership with Pfizer could help speed the trial up and could result in changes to the trial design.