In the Lab

On Cancer: New Molecule Targets Proteins Inside Cancer Cells

By Julie Grisham, MS, Science Writer/Editor  |  Wednesday, March 13, 2013
Pictured: ESK1 Monoclonal Antibody The ESK1 monoclonal antibody was engineered to recognize WT1 peptides brought to the surface of cancer cells.

Scientists from Memorial Sloan Kettering have discovered a unique monoclonal antibody that appears to be very effective at targeting and destroying several types of cancer cells. The research was done in collaboration with the California-based biotechnology company Eureka Therapeutics and was reported March 13 in Science Translational Medicine.

Monoclonal antibodies are molecules that can be engineered to target specific proteins on cancer cells. A number of them are already available to treat a variety of different cancers. The new monoclonal antibody, called ESK1, targets a protein that is associated with many types of cancer and is of great interest to cancer researchers.

Because of their large size, monoclonal antibodies can target only proteins located on the outside of cancer cells. But ESK1 is different because it is capable of recognizing the presence of a protein that resides within the cell. This is a long-sought goal for this important class of anticancer agents, since most proteins that cause cancer or are associated with the disease are buried inside cancer cells.

An Important Cancer Target

“This is a new approach for attacking an important cancer target with an antibody therapy. This is something that was previously not possible,” says David A. Scheinberg, Chair of the Sloan Kettering Institute’s Molecular Pharmacology and Chemistry Program and an inventor of the antibody. “Our research shows that you can use a monoclonal antibody to recognize a cancer-associated protein inside a cell, and it will destroy the cancer cell.”

ESK1 targets a protein called WT1, which is overexpressed in a range of leukemias and other cancers including myeloma, mesothelioma, breast cancer, ovarian cancer, and colorectal cancer.

WT1 is a critically important target for cancer drugs because it is an oncogenic protein, meaning that it supports the formation of cancer. In addition, it is found in very few healthy cells, so there are less likely to be side effects from drugs that target it.

Mimicking the Immune System

ESK1 was engineered to mimic the function of T cells, white blood cells that are key components of the immune system. T cells have a receptor system that is designed to recognize proteins that are inside the cell.

As proteins inside the cell get broken down as part of regular cellular processes, molecules known as HLA molecules carry fragments of those proteins — known as peptides — to the surface. When T cells recognize certain peptides on the surface of cells as abnormal, the T cells kill the diseased cells.

In the current study, the investigators showed that ESK1 was able to recognize the WT1 peptide even though the antibody itself did not enter the cells. ESK1 killed cancer cells in a test tube and also in mouse models for two different types of human leukemia.

“We were surprised that the antibody worked so well on its own,” says Dr. Scheinberg, senior author of the paper. “We had originally expected that we might need to use the antibody as a carrier to deliver a drug or a radioactive therapy to kill the cancer cells, but this was not necessary.”

Advancing to Clinical Studies

Additional studies must be done in the laboratory before ESK1 is ready to be used in clinical trials for patients. The monoclonal antibody was engineered to be completely human, which should shorten the time it takes to move the drug into the clinic. Researchers expect that the first clinical trials, for leukemia, could begin in about a year.

The antibody was developed under a collaborative effort between Memorial Sloan Kettering and Eureka Therapeutics, which have jointly filed for patent protection.

Research is also under way to target WT1 with vaccines and engineered T cells.  These therapeutic approaches are currently in clinical trials at Memorial Sloan Kettering for leukemia, multiple myeloma, ovarian cancer, and mesothelioma.

This work was supported by grants from the Leukemia and Lymphoma Society, the National Cancer Institute (under award numbers CA23766 and CA55349), the Sloan Kettering Institute’s Experimental Therapeutics Center and its Technology Development Fund, the Commonwealth Foundation for Cancer Research, the Tudor and Glades Foundations, the Merker Fund, the Lymphoma Foundation, and the Mesothelioma Applied Research Foundation.

Comments

Will this work on Hodgkin's Lymphoma or the other Lymphomas?

Thank you for your comment. This research is in the early stages, and additional studies must be done in the laboratory before ESK1 is ready to be used in clinical trials for patients.

What is the estimated time frame for solid tumor trials?

Thank you for your comment. We spoke with Dr. Scheinberg, who said that these trials may not begin for at least one to two years.

My boyfriend is at Robert Wood Johnson MD PHD program in New Jersey. He has done research in this area by targeting CA cells and very similar work to this study. Is there a way to get in touch with the scientist who has done this work? Thank you. I appreciate your time. The every day work of scientists is phenomenal and the hard work should be recognized and appreciated.

Thanks for your comment. You can see more information about Dr. Scheinberg here: http://www.mskcc.org/research/lab/david-scheinberg.

I had breast cancer stage 2 in 2006. I now have ovarian cancer stage 4. I would like to be considered for the clinical trial.

You can find a list of our ovarian cancer trials here: http://www.mskcc.org/cancer-care/clinical-trials/clinical-trial?keys=ovarian+cancer&field_trial_diseases_value=All If you would like to make an appointment with a Memorial Sloan-Kettering doctor, please call 800-525-2225. Thanks for your comment.

Will this work on AML?

Thanks for your comment. Dr. Brentjens says: "We’re working in the lab on generating a receptor to target AML tumor cells. Unfortunately, we don’t expect such a trial to open for several more years."

I am writing regarding my dear friend and spiritual sister Cathy Davis. We both have suffered from colon cancer. Hers has responded well to chemotherapy and radiation. unfortunately, she developed another form of lung cancer and recently she was told there is nothing they can do will this new molecular system work for her she needs immediate help? We are desparate and hope you can advise us.

This antibody is still experimental, and it is too early to know which types of cancer it may be able to treat. If your friend would like to make an appointment to talk with a doctor at Memorial Sloan-Kettering about other treatment options, she can call 800-525-2225. Thanks for your comment.

Thank you for this information it is very hopeful how can we get enrolled in this trial treatment, Who can we contact, can you provide a number as time is running out please help.

If you would like to make an appointment or learn about clinical trials at Memorial Sloan-Kettering, please call 800-525-2225. Thanks for your comment.

I wish, the monoclonal antibody ESK1 trial is extended for the treatment of clear cell renal cell carcinoma.

Check out this protein research group http://boinc.bakerlab.org/rosetta/

Is there anything new for neuroendocrine tumors?

Gail, you can find more information about gastrointestinal neuroendocrine
tumors here: http://www.mskcc.org/cancer-care/adult/gastrointestinal-neuroendocrine-tumors.
You can find more information about pulmonary neuroendocrine tumors
here: http://www.mskcc.org/cancer-care/adult/pulmonary-neuroendocrine-tumors.
If you'd like to make an appointment with a Memorial Sloan-Kettering doctor,
please call 800-525-2225. Thanks for your comment.

I am so pleased to read this. You are doing Gods work. My wife has Stage 4 Breast Cancer but her A-C Chemo has pretty much gotten rid of it - for now. It must be heart breaking to have a possible cure and turn people away. No one wants to be the last soldier killed in a war.

This seems a encouraging breakthrough by Memorial Sloan-Kettering. My sister has Ovarian Cancer and next month she will go in for surgery. Recurrence being the sad possibility will there be any clinical trials for Ovarian Cancer patients?
Thanks
Sanjev

Thanks for your comment. You can find a complete list of clinical trials for ovarian cancer here: http://www.mskcc.org/cancer-care/adult/ovarian/clinical-trials.

Hi, my husband was found to have gall bladder cancer in November 12 following laparoscopic removal of his gall bladder. Following that he has under gone liver resection surgery and a 6 week radiation/ chemo treatment to the lymph area around the portal vein and vena cava. His first post treatment CT Scan has shown changes in the lymph area of the peritoneum. Is there any treatments/ trials that may assist him. We are in Australia and will we are travelling to NYC in early June. We would appreciate being able to meet with anyone who can help us understand any advancements or research into treatment of this type of cancer. Thank you for your consideration.

Thanks for your comment. You can find our information for international patients here: http://www.mskcc.org/cancer-care/international-patients. We suggest that you review this information and contact us as soon as possible.

My brother has just been diagnosed with small cell cancer in the lung, liver and bones. Is there anything new being tried for this aggresive cancer? He has been given 2 mos. without treatment, 8mos. with chemo. Please reply asap. Thank you.

Clare, you can find a list of our clinical trials for non-small cell lung cancer here: http://www.mskcc.org/cancer-care/clinical-trials/clinical-trial?keys=&field_trial_diseases_value=Lung+Cancer%2C+Small+Cell If you would like to make an appointment at Memorial Sloan-Kettering, you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thank you for your comment.

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