New Drug Developed at MSK Starves Acute Myeloid Leukemia of a Signaling Fix

By Matthew Tontonoz,

Monday, January 18, 2016

Light micrograph of white blood cells from a patient with acute myeloid leukemia.

A drug called PU-H71, developed at MSK, targets an altered version of a protein that some acute myeloid leukemia cells need to grow. Blocking the action of this protein may be an effective way to treat these cancers. New research from MSK sheds light on which patients may respond best to the drug.

  • AML is a rare, often deadly cancer that frequently returns after frontline therapy.
  • Aggressively growing AML cells require a molecule called Hsp-90 to function.
  • A drug called PU-H71 specifically blocks the action of Hsp-90 in cancer cells.
  • Patients with AML that is most dependent on Hsp-90 may respond best to the drug.

For patients with acute myelogenous leukemia (AML), a rare blood cancer, the biggest problem is relapse following initial treatment: The cancer resurges in about 85% of cases, usually causing death.

Memorial Sloan Kettering chemical biologist Gabriela Chiosis is hoping to change that grim statistic.

For several years, Dr. Chiosis has been developing a new drug — dubbed PU-H71 — that she hopes will provide more durable control of the disease. In a recent paper published in Cell Reports, Dr. Chiosis and her colleague Monica Guzman of Weill Cornell Medical College present new findings that help explain why PU-H71 kills some AML cells but not others.

PU-H71 didn't come out of screening existing chemicals. It's a compound unknown to man or nature.
Gabriela Chiosis
Gabriela Chiosis chemical biologist

The drug is most effective at treating AML cells that are “addicted” — the technical term — to a particular network of signals in the cell. By disrupting this network, the drug removes crucial support that leukemia cells need to grow.

PU-H71 is already being tested in clinical trials, and the new research may help doctors select the most appropriate patients to receive it. 

Designer Drug

The drug Dr. Chiosis studies is not a chemical that existed in the world before she created it. “PU-H71 didn’t come out of screening existing chemicals,” Dr. Chiosis says. “It’s a compound unknown to man or nature.” 

She designed the drug by first looking at the structure of the target she wanted to hit — a protein called Hsp90. Using computer-aided models to visualize its structure, she found that Hsp90 had a distinct “pocket” that made it a particularly tempting target for a structurally minded chemical biologist like her. “I looked at the pocket in the protein and mentally designed a chemical to fit in it,” she says.

The first time she tested her newly built chemical, it behaved just the way she hoped it might — blocking Hsp90 in tumor cells from binding ATP, and therefore from doing its job. Years of additional chemical optimization eventually resulted in the drug PU-H71.

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Addicted to Signaling

Like all cancers, AML is driven by mutations that lead cells — in this case, white blood cells — to divide uncontrollably. Many of these mutations affect proteins that are part of signaling networks that communicate important messages through the cell. Cancer results from inappropriate activation of these signals — including, for example, signals for growth that are permanently stuck “on.”

As AML becomes more aggressive, it grows more addicted to these growth signals — and therein lies a weakness that scientists can exploit. Interrupting this network of signals deprives the cancer cells of their signaling “fix,” cutting them off cold turkey.

How can a single drug such as PU-H71 affect multiple signaling proteins at once? Many proteins require the assistance of special molecules called chaperones that help them fold properly and guide them to the right place in the cell. Hsp90 — the target of PU-H71 — is the particular chaperone that assists most signaling proteins. Blocking the action of Hsp90 disrupts all the signaling proteins that depend on it.

Unlike many other anticancer drugs, including many chemotherapies, PU-H71 kills cancer cells specifically. That’s because PU-H71 targets a form of Hsp90 found only in cancer cells, leaving normal cells unaffected. That means less toxicity for patients.

PU-H71 targets a form of Hsp90 found only in cancer cells, leaving normal cells unaffected.

And, because a whole network of signals is disrupted rather than just one or two, it should be much harder for cancer cells to develop resistance to the drug. 

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Selecting the Appropriate Patients

Not all AML cells respond equally well to PU-H71, raising the question of which patients should receive it. With other targeted drugs, such as BRAF inhibitors in melanoma or Herceptin in breast cancer, it’s clear who should get the drug: individuals with a BRAF mutation or HER2 overproduction. But for AML, there is no one mutation that correlates with response to PU-H71, a fact that has plagued drug development efforts. 

“Over 20 Hsp90 inhibitors have entered clinical testing, but they have progressed very slowly because it has not been possible to figure out the right patients to target,” Dr. Chiosis says. “If your therapy works on only 10 percent of patients, you need to know who those 10 percent are.”

If your therapy works on only 10 percent of patients, you need to know who those 10 percent are.
Gabriela Chiosis
Gabriela Chiosis chemical biologist

Dr. Chiosis’s research suggests that only patients with AML cells that are highly addicted to signaling networks will respond to the drug. Targeting just these cancers provides a way to tailor the treatment to the patients most likely to respond.

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A Big Step Forward

The new research would not have been possible without extensive collaboration across multiple labs and disciplines. “You really have to put people from different fields and with different minds together to get to a great answer,” Dr. Chiosis says. “Otherwise, you’re always stuck with the little answer and only little steps forward.” 

In addition to her collaboration with Dr. Guzman of Weill Cornell, Dr. Chiosis worked with basic scientists and clinicians in several other departments at MSK. The strong support for translational research that bridges basic and applied science has been crucial to the success of the project, she says.

“There aren’t many places you can take something all the way from a computer screen to the clinic,” she notes.  

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This research was funded by grants from the National Institutes of Health and the Experimental Therapeutics Center of MSK. MSK holds the intellectual rights to PU-H71. Samus Therapeutics, of which Dr. Chiosis has partial ownership, has licensed PU-H71.


Is this protocol used for AML M3--Acute Promyelocytic Leukemia?

Dear Mary,
PU-H71 is currently being tested in a phase I trial for patients with advanced solid malignancies and lymphoma ( Patients with AML are not eligible for this trial, although several phase II trials are currently being planned, including one for AML. The study discussed in this blog post provides information that will be useful to doctors when AML trials open.
For more information about clinical trials being conducted at MSK, please visit our clinical trial site:

Thanks for your comment.

Dr. Abou-Alfa and his staff are world-class professionals who have always demonstrated great compassion for their patients. I am privileged to be in their care.

Raymond, we're so glad to hear you feel well cared for. We'll share your message with Dr. Abou-Alfa.

My mother died of AML. I also knew a couple of other people who had AML who died. The only one who survived was my daughter in law's friend who had a bone marrow transplant. I'm so glad that there is a drug to look forward to that will help eradicate this cancer!

This is such incredible news! My daughter Dana died from complications from Perhiperal stem cell transplant for AML in 2004. Can you tell me if this new drug can me used to treat AML with Monosomy 7 markers? I will keep your team in my prayers and I know Dana will too. Bill Hall

Dear Bill,
We're so sorry to hear about your daughter. We hope this drug may one day help patients with AML. As of yet, only one study of PU-H71 is currently enrolling patients: AML is not eligible for this particular trial, but several phase II trials are currently being planned, including one for AML.

Bravo Dr. Chiosis and to your team as well. My beloved husband Peter died from complications of his stem cell transplant for AML and MDS in 2010. GVHD - Gut. It is brilliant innovative scientists like Dr. Chiosis and many others in the cancer community who will beat this demon once and for all someday. Keep fighting!

We're very sorry for your loss. Thank you for your kind words.

my Husband was diagnosed with AML in July 2015, he had a Bone Marrow Transplant at the end of October 2015, his Sister was the Donor, he is now doing aTrial Pro T4, good Luck with all your research, you all do A Fantastic Job, much Love, Wendy Xxx

Wendy, we wish your husband our best as he continues with his treatment. Thank you for your kind comments.

It is important have a new medication

My mother, Sara, died of AML at the age of 51 in October of 2007.

It gives me hope and comfort that researchers and doctors are trying to find more treatments for these cancers. No one should have to lose their family this way.

Dear Meredith, we are very sorry for your loss. Thank you for sharing your thoughts on our blog.

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