Anti-HIV’s now also anti-cancer ?

Its been a while since I last updated here, and there are many potential off-label drugs for cancer that should be NEXT written about, but one category that deserves immediate attention are the anti-HIV drugs.  One of them, Nelfinavir, was even called “a magic bullet to annihiltate cancer cells” recently (Cancer Biol Ther. 2009 Feb;8(3):233-5).

Of course, cell signalling pathways as a source for new target therapy drugs against cancer is all the rage now but to develop a new candidate molecule into an approved drug can cost a billion dollars and take over 10 years, so how about looking at established targeted therapies for other diseases such as HIV and see if there are potential off-label drug candidates for cancer there ?  Well, Dr. Phillip Dennis and colleagues did exactly that:  they took existing HIV protease inhibitor drugs and tested 6 of them against cancer cell lines derived from 9 different human tumor types and found that three of the drugs (ritonavir, nelfinavir and saquinavir) reduced the growth of 60 of those cell lines. In the laboratory, nelfinavir or Viracept®, a first generation speific protease inhibitor designed for HIV appeared most potent (Autophagy 4(1):107-9, 2008).

Nelfinavir seems to exercise a broad-spectrum cancer killing effect through multiple pathways: apoptosis, necrosis and autophagy (See Clin Cancer Res 13(17): 5183-94, 2oo7), and is also noted to have antiangiogenic and immunomodulatory ability.  Nelfinavir has also been shown to have radiosensitizing properties (Cancer Res. 2005 Sep 15;65(18):8256-65.) via Akt activation making it a logical addition to radiation therapy and trials using it in this fashion are underway against brain, rectal and pancreas cancers.  One of the ways it works with chemo and radiation may be via disruption of the process by which hypoxia occurs by restoring proper blood flows to tumors ad making them more vulnerable to other therapies according to research by McKenna of Oxford. McKenna’s group also demonstrated as early as 2005 that Nelfinavir radiosensitized cancer cells and a small trial he conducted with nelfinavir + chemoradiation showed dramatically that 6 out of 10 patients with advanced pancreas cancer had their cancer shrank enough to be surgically removed whereas normally it would be only 1 in 10 (J Clin Oncol. 2008 Jun 1;26(16):2699-706) .

Using anti-HIV drugs against cancer is not a novel idea, the grand daddy anti-HIV drug AZT was originally tested against cancer in the ’90s because of laboratory promise, but it did not pan out in human testing.  HIV patients are at increased risk for certain cancers, and those on protease inhibitor treatment have been thought to have reduced kaposi’s sarcomas and lymphomas, this observation was noted early on and trials to test the drugs against HIV related cancers were planned as early on as 2003 in Italy (Lancet Oncol. 2003 Sep;4(9):537-47)

The anti-HIV protease inhibitors have been around since 1993 and their dosage, safety and toxicity in humans are well known.  Currently, multiple phase 1/2 studies are under way to evaluate the potential of nelfinavir in renal cell, rectal, lung, adenocystic, liposarcoma, brain and pancreas cancers, alone, and in combination with chemotherapy and radiotherapy and other targeted agents such as bortezomib or Velcade® and temsirolimus or Torisel®. (See current US trials here)

The usual starting dose for nelfinavir is 1250 mg twice a day (costs about $25/day in the US) but ongoing phase 1/2 trials are testing higher doses.  Its common side-effect is diarrhea, blood lipid abnormalities  (good reason to add a statin as another off-label anti-cancer treatment, see here; but caution must be exercised when adding or selecting a statin due to potential drug-drug interaction via the CYP pathway where the lactone pro-drugs simvastatin and lovastatin should not be used, see here) and redistribution of body fat (64% at 13 months of usage), as well as glucose intolerance (with a diabetes risk of 3% with long-term use) but its side-effects do not overlap with mainstream anti-cancer agents’ and is usually tolerable for long term treatment.

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