Molecular Profiling (incl Phosphorylated Receptors) in ASPS

[Fictional]

Here's our latest molecular profiling result - from a lung nodule removed 3 wks ago by Dr. Rolle. We were able to use a special fixative (Phosphoguard) that is supposed to preserve phosphorylated receptors (so identifies activated receptors, not just the presence of receptors).

The summary:

Ki67 2+ positive, 22% tumor cells
c-met 1+ positive, 80%
VEGF 2+ in 30%
c-kit neg
ER neg
HIF-1a 3+ positive, 50% cells
IGFR-1RB 2+ positive, 50% cells
PDGF (a&B) 1+ positive, 70% cells
PTEN 2+ positive 50% cells
Phospho-4E-BP1 3+ staining in 30% cells
Phospho-AKT 1+ staining 40%
Phospho-EGFR 1+ staining in 30%
Phospho-SRC 2+ staining in 20%
Phospho p44/42 MAPK in 10%
Topoisomerase II Alpha 2+ in 20%
thymidylate synthase 2+ in 20%

The main conclusions from this were that anti-angiogenesis remains the way to go (that is why we are on metronomic vinblastine + cytoxan), but in addition, our biotech CEO said that the c-met-HIF1-alpha axis looked like a reasonable therapeutic target to add on to an existing antiangiogenic regimen...if possible. Met apparently induces HIF-1alpha, both of which may facilitate metastasis and angiogenesis. So bottom line, we will try to obtain permission from Arqule to add ARQ197 to our existing regimen, but that may be tough. We will say that our doses of the vinblastine and cytoxan will not be immunosuppressive...rather antiangiogenic, as one of the exclusions for the trial was being on immunosuppressive drugs. It might be a long shot, but 'K' had her unique protocol anyway, we will try. It seems like it would be an ideal combination.

The way my friend said they usually interpret the profiling results is to take the % cell stained and multiply by the intensity (maximum would be an H score of 300). Usually scores of 150 or above are potential strong targets.

Another possible candidate in the list was IGFR - she had mentioned Amgen and Pfizer have IGFR blockers...and I know that R1507 seemed to have a good safety and side effect profile when I looked before.

I noticed some markers for the mTORs, but told her I was concerned that a woman with ASPS on the forum a few years ago initially had what looked to be a very good response to rapamycin, but then when the med was stopped to do a biopsy, the cancer grew rapidly and she died. She told me rapamycin and Torisel are older drugs that only block one of 2 mTorc proteins. Now they know that if you only inhibit one, it can allow the other one to dramatically increase their activity. Better candidates may be drugs like RAD001...that block both mTorc 1 & 2...but of course this would be safer if we know of other patients who have benefited from them already.

I asked her about EGF as the recent sutent paper also noted phosphorylated EGFRs in ASPS...she said it would be less attractive of a target because EGF is everywhere...and thus far clinically EGF blockers have only been effective if the cancers highly overexpress EGFRs or EGFRs are amplified. Apparently < 5% cancers overexpress EGFRs.

Finally, we talked about rebound effects in antiangiogenesis agents. She told us she knows that Avastin can rebound in breast cancer if the cancer is not virtually entirely killed off. She did not know of that effect with other agents or cancers.

I did mention that recent data from mice about anti-angiogenesis agents and possible increased metastastic potential...and she said they have not seen that clinically with the agents...and now these agents have been given to patients x years. I did hear they recently halted the phase III cross-over trial with Sutent because its benefit was so marked they did not want to take the treatment arm off the drug.

Finally, she said that the Ki67 (22%) supported metronomic dosing...lower doses for longer durations rather than high doses for shorter cycles. On 'K''s last thoracotomy, the necrotic nodules were the ones with the highest Ki67 values (50% etc)...