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Aurora Kinase Inhibitors as a Novel Anti-Cancer Approach
One emerging class of targeted therapy for cancer that is just entering clinical trials is a group of agents called aurora kinases. A kinase is a protein that modifies the structure and function of other proteins by adding a phosphate group to it, which is like flipping an on/off switch. Aurora was discovered by Dr. David Glover and colleagues at the University of Cambridge, who found that the protein is involved in the normal process of mitosis (cell division after duplication of the DNA), and that mutated forms of the proteins led to disruption of normal cell division. Because it is involved in the polar regions of the cell, it was named Aurora after the aurora borealis, or northern lights:
(click to enlarge either) 
Aurora was later found to exist in three different forms in humans (A, B, & C), all involved in parts of the cycle of cell division, including how chromosomes move around in the dividing cell. Because cancer cells tend to divide faster than normal cells of the body, proteins that disrupt the process can preferentially harm cancer cells before non-cancer cells in the body. Continue reading
Bisphosphonates for Skeletal Metastases in Lung Cancer
In addition to local treatments such as surgery or radiation for more immediate and directed therapy for bone metastases, there is a commonly used and FDA-approved approach with Zometa, also known as zoledronate or zoledronic acid. It is one of a class of drugs known as bisphosphonates that can reduce the rate of progression with skeletal complications. They bind tightly to calcium and then distribute especially to sites of active bone remodeling, such as bone metastases. In addition to increasing calcium deposits in bone, bisphosphonates like Zometa and others inhibit cells called osteoclasts, which break down bone (and can have a normal function in remodeling during the healing process for bone).
More than 10 years ago, clinical trials with other bisphosphonates demonstrated reductions in the risk of future skeletal fractures and pain in patients with osteoporosis and cancer-related bone disease. A key trial, known as Zometa 011 (abstract here) evaluated Zometa at either 8 or 4 mg given IV every three weeks for 9 months, compared with a placebo in patients with bone metastases from lung cancer or another solid tumor. A total of 773 patients were enrolled, of whom 436 had lung cancer (378 with NSCLC, 58 with SCLC), representing by far the largest cancer type involved in the study. Participants also received supplemental calcium with vitamin D. In an earlier safety analysis, it was noted that patients on the higher dose of zometa were experiencing problematic declines in their kidney function over time, and the trial was modified to focus exclusively on the lower dose of 4 mg IV every three weeks. The trial was also modified to give the Zometa or placebo over 15 minutes instead of 5, since this had been found in other testing to be associated with lower risk of kidney problems. Continue reading
Targeted Therapies in Lung Cancer Conference
I’ve been covering bone metastases for the past several posts, because it’s an important topic that affects lots of people with cancer, and because there are many approaches that can potentially be involved. I’ll finish my coverage of that topic with one more post.
In the meantime, I’m in LA now to speak at and attend the 6th Targeted Therapies for the Treatment of Lung Cancer Conference, sponsored by the International Association for the Study of Lung Cancer, or IASLC. It has the unusual format of including dozens of presentations on novel targeted agents and approaches for lung cancer, including some that are still in animal models. The speakers get only 5 minutes to cover a topic with 3-5 slides, so we can’t go into much depth. However, I’ll relay highlights of some emerging agents for everyone in the coming weeks.
Sunitinib/Sutent in NSCLC
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. Continue reading
Sorafenib/Nexavar in Non-Small Cell Lung Cancer
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. Continue reading
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