HSP 90 Inhibitors: Another Rational Choice for Patients with Acquired Resistance to EGFR Inhibitors

Dr. Johnson

Continuing Dr. West's theme discussing new therapies for patients with acquired resistance, I'd like to answer a few questions about HSP 90 inhibitors that have caught my attention on GRACE over the past few weeks, and in particular, highlight my "pet" targeted agent, AUY922. HSP 90 inhibitors are drugs that many of you already know about-they are being studied in patients with ALK(+)lung cancer and as a 2nd line therapy option for all patients with lung cancer with Taxotere. But what you might not have known previously is that there is pre-clinical evidence that they may be also useful for patients with EGFR (+) lung cancer, with acquired resistance to Tarceva.

HSP 90 proteins are "chaperone proteins"-they form partnerships with other proteins-"client proteins"-- in order to guide the folding or bending of client proteins into the shapes necessary for normal protein activity. Although many, many proteins require HSP 90 chaperones for normal metabolism (ie., making a cell's world "go round"), in particular those proteins which activate cancer development ("onco-client proteins") can form complexes with HSP 90 chaperones -and they stay bound 100x more tightly once snuggled into their chaperone-client complexes. As a result, the onco-clients can remain "stable", or focused on their mission of driving malignant cells to form tumors.

hsp90-client-proteins (click on image to enlarge)

Above you'll see a cartoon illustrating a number of different proteins responsible for driving cancer cell survival and metastasis. All the proteins shown in red are onco-clients that require HSP 90 chaperones. You'll notice that both EGFR and MET require HSP 90 chaperones (ALK does too, though not illustrated here) in order to fold and function. Therefore, you might ask "what happens if you get rid of that chaperone?"

Enter HSP 90 inhibitors. There are many HSP 90 inhibitors in development that you may have heard of: AUY922, IPI504, STA9090, SS-2248 to name a few. (Geldanamycin, 17 AAG, and 17 DMAG are older "parent" compounds of the same thing). When mice with EGFR (+) tumors with T790M or EGFR (+) tumors with MET amplification were treated with HSP 90 inhibitors, the tumors shrunk. We thought it would be interesting to study HSP 90 inhibitors and Tarceva in humans, and Novartis agreed to partner with us to study their HSP 90 inhibitor AUY922 in patients with acquired resistance.

Why continue the Tarceva in patients with acquired resistance? There are lots of anecdotal reports (and a couple of published papers) describing a disease "flare" for patients who stop their Tarceva after developing acquired resistance-either in terms of worsening clinical symptoms or in rapid radiographic progression of disease. The current hypothesis of acquired resistance is that it is a heterogenous syndrome that develops in different patients at difference places in the body, and not likely all of a sudden, but more gradually. As a result, many of us lung oncologists will continue Tarceva even as we start a 2nd line treatment in patients who have developed acquired resistance-- to avoid any disease flare, and to capitalize on any remaining benefit from Tarceva.

For this reason, I wanted to test AUY922 added to Tarceva. However, this combination had not been tested before in humans. Therefore, the first step was to submit an IND (Investigational New Drug) application to the FDA for permission to study AUY922 and Tarceva in combination. Next, we opened the dose-escalation phase I study to find the "best" dose of each drug when given at the same time.

auy922-with-erlotinib

Currently, we’ve treated 3 patients at each of the 1st and 2nd dose levels. We’re hoping to step up to the 3rd dose level in mid-November. One of the side effects we were most worried about was the diarrhea-- since both AUY922 and erlotinib can cause this. It was out of concern for causing horrible diarrhea that we had to start each drug at a lower dose than it would have been given individually. Fortunately, all diarrhea patients have reported has been manageable so far.

Based on prior experience with other HSP 90 inhibitors, we were also worried about whether AUY922 would cause any abnormalities in the heart’s electrical “firing”, or conduction system, and whether AUY922 would cause visual changes such as “floaters”, and/or difficulties accommodating (going from light places to dark places). No problems yet with anybody’s heart rates. The first hint of visual changes came just last week in one patient—and so we’ll be watching that closely going forward.

In order to be enrolled in this trial, patients all undergo a re-biopsy at a site of disease that has grown while on Tarceva alone. This tumor tissue will be tested for T790M, MET amplification and HGF (a partner with MET in cancer cells). This “side-car” project will help us figure out which mechanism of acquired resistance is/are being affected with inhibition of HSP 90.

This trial is open at Northwestern University in Chicago and at Memorial Sloan-Kettering in NYC. I am excited to say that accrual has been going really well, considering only three patients can be enrolled at once-- on a dose-escalation trial, safety is the paramount focus. If the phase I study continues like it’s going now, I am hopeful that we’ll open a larger phase II study more focused on efficacy sometime next year. Stay tuned!

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