While there have been studies of the COX-2 inhibitor celebrex in combination with chemo for treating NSCLC, the palpable buzz about celebrex in treating lung cancer has been from a trial by my friend Karen Reckamp, formerly at UCLA, now recently moved to City of Hope Cancer Center in nearby Duarte, CA. Several studies have shown that EGFR expression is associated with increased cell growth, increased angiogenesis, increased tissue invasion and metastasis, and a worse survival compared with patients who have tumors that don’t overexpress EGFR. And as I wrote in my introductory post on COX-2 inhibition, high expression of this enzyme can also lead to worse patient outcomes among folks with NSCLC (COX-2 actually hasn’t been shown to be expressed significantly in SCLC). In fact, these two pathways interact to regulate cell proliferation, migration, and invasion (reference article here).

(complex, isn’t it? Click to enlarge — but it won’t help, unless you’ve got a PhD in biochemistry)

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Sunitinib (SU11248), with the marketing name Sutent, is another multikinase inhibitor, an oral agent that blocks several potentially important anticancer targets in the cell with one drug. This drug is FDA-approved in treating advanced kidney cancer and also a cancer called GastroIntestinal Stromal Tumor (GIST) after progression or intolerance of Gleevec (imatinib). It inhibits the tumor blood supply by blocking the Vascular Endothelial Growth Factor (VEGF) Receptor family, and it can inhibit cancer cell growth by blocking a target called Platelet-Derived Growth Factor (PDGF) Receptor, as well as some other growth signal targets:

(Click to enlarge)

We know that greater expression of both VEGF and PDGF by cancers are associated with worse survival. In fact, you can see the remarkable difference in survival for patients in a European study of 120 stage I patients who underwent surgery and then had their tumors stained for VEGF expression and the functional correlate of it, microvessel density (the density of small blood vessels in the tumor, which are induced by VEGF), divided into levels above or below the median (half-way point):

WOW! Huge difference. This test isn’t routinely available, at least not yet. Read the rest of this entry »

Sorafenib, or Nexavar, is an oral “multi-kinase inhibitor”. Kinases are specialized proteins that coordinate communitcation networks inside the cell and can modulate cancer cell growth as well as angiogenesis, the tumor blood supply. While many of the molecularly targeted agents I have discussed previously have demonstrated activity in lung cancer and sometimes other tumors, I have been discussing agents that primarily target one important cell process or another. Multi-targeted agents can potentially affect multiple relevant signaling cascades at once, but it isn’t clear yet whether they work better than our single-targeted options, or combinations of several single-targeted drugs together. There may also be the possibility of developing new combinations of side effects from one agent that hits multiple targets at once.

Great, but does it work? Fortunately, it does, at least in some tumor types. Sorafenib is currently approved by the US FDA for treatment of advanced kidney cancer, where it was studied in a randomized, placebo (sugar-pill) controlled trial of over 900 previously treated patients. This trial demonstrated that patients treated with nexavar at 400 mg by mouth twice daily went more than twice as long before developing progression of disease compared to the patients who received a placebo. There was also an improvement in overall survival in patients who received nexavar. It was generally well tolerated, with the main side effects being diarrhea, rash, fatigue, a “hand/foot syndrome” of redness and burning on the palms and soles, hair loss, and nausea/vomiting. Read the rest of this entry »