Scientists Home in on Treatment Advance for Chemotherapy-Resistant Small Cell Lung Cancer

By Matthew Tontonoz,

Monday, February 13, 2017

MSK scientists Charles Rudin and John Poirier
Summary

Small cell lung cancer (SCLC) is notoriously difficult to treat because it quickly acquires resistance to chemotherapy. Scientists at Memorial Sloan Kettering have uncovered a molecular mechanism by which SCLC cells develop resistance, opening the door to new treatments.

Highlights
  • A newly uncovered mechanism explains how SCLC develops resistance to chemotherapy.
  • The mechanism involves an epigenetic change — one that does not result from DNA mutations.
  • Drugs that target this mechanism are currently in clinical development and could be combined with chemotherapy in new trials.

The statistics surrounding small cell lung cancer (SCLC) are grim. Nearly everyone diagnosed with the disease dies from it, and the average survival time for someone with metastatic disease is less than one year. New therapeutic options are badly needed, yet the disease has proved stubbornly resistant to treatment advances.

“We haven’t really had substantial change in the standard of care for this disease in 30 or 40 years,” says Charles Rudin, Chief of the Thoracic Oncology Service, Co-Director of the Druckenmiller Center for Lung Cancer Research, and holder of the Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering.

But there are promising signs that the situation may be changing. A study published today in the journal Cancer Cell, led by senior authors Dr. Rudin and John Poirier, identifies a potential new way to combat the disease’s most wily attribute: its ability to rapidly develop resistance to chemotherapy.

“Although SCLC is incredibly chemosensitive initially, those responses are almost never durable and the disease comes roaring back,” explains Dr. Rudin. “When it does, it’s very resistant to treatment.”

The team has homed in on what they think is a switch that promotes resistance, and a class of drugs that can flip it back in the other direction.

Hunting for Differences

To answer the question of what accounts for the development of resistance, the team turned to mouse models of cancer. They implanted mice with patient-derived SCLC tumors to create so-called xenografts. Mice carrying chemosensitive xenografts were treated with a chemotherapy regimen similar to what patients receive in the clinic until the tumors developed resistance. The team then performed a side-by-side comparison of the tumor cells’ genetic makeup and gene expression profiles.

To their surprise, the main difference between the chemosensitive and chemoresistant tumors was not specific genetic mutations — changes in the DNA sequence — but rather the production of a particular protein called Schlafen 11.

Schlafen 11 is known to sensitize cancer cell lines to chemotherapy and is thought to play a role in how cancer cells respond to DNA damage — such as the kind that occurs when cells are treated with chemotherapy. When Schlafen 11 production goes down, cells can tolerate DNA damage more easily. This allows them to survive treatment with DNA-damaging chemotherapy, and therefore to become chemoresistant.

Lung Cancer
If you or your loved one has been diagnosed with lung cancer, Memorial Sloan Kettering is ready to help. Find a doctor and learn about our treatments today.
Learn more

The production of Schlafen 11 is controlled by a process called histone methylation. In cells, DNA exists wrapped around proteins called histones that act as spools; how tightly wound and compact the DNA is can influence whether genes in that region are turned on or off. As the cancer cells are exposed to chemotherapy, they begin to accumulate a protein called EZH2, which transfers methyl groups to histones. This compacts the DNA and, in turn, silences genes. One of the genes turned off by this mechanism is Schlafen 11.

This is an example of an epigenetic change, one that alters the way genes are turned on or off in the cell — in this case, through the accessibility of the DNA — without changing the DNA sequence itself.

Though the researchers didn’t start out looking for an epigenetic mechanism to explain the development of chemoresistance, it fit well with the clinical picture.

“We know that in our models, and in the clinic, the emergence of acquired resistance can happen fairly quickly,” says Dr. Poirier. “So an epigenetic mechanism that converts already existing tumors to a more resistant phenotype made sense to us.”

The team confirmed the role of Schlafen 11 by showing that they could convert a chemoresistant tumor into a chemosensitive one by restoring the expression of this protein experimentally.

Back to top

Drugs Already in the Pipeline

What most excites the researchers about this new finding is that there are drugs currently in clinical testing that block the action of EZH2. The drugs appear to be safe in people, so the researchers are eager to perform clinical trials. The plan is to test a combination of standard chemotherapy plus an EZH2 inhibitor, with the hope of forestalling — or even preventing — the development of chemoresistance in SCLC. 

“It’s clear that an EZH2 inhibitor can reproducibly turn Schlafen 11 back on and that the magnitude of re-expression is strongly correlated with the degree to which these tumors are re-sensitized to chemotherapy,” says Dr. Poirier. “So we feel very confident in the pathway and the pharmacologic approach.”

The team is in the process of designing a phase I clinical trial. 

Back to top

Making Inroads

Dr. Rudin says the discovery represents the kind of collaborative, translational research he wanted his lab to pursue when he came to MSK three and a half years ago. “Dr. Poirier and I came together from Johns Hopkins with the idea of co-directing a laboratory because we think we have complementary strengths to offer,” he says — he as a clinical and translational investigator and Dr. Poirier as a basic scientist with expertise in molecular biology and bioinformatics. “We felt that this was a problem that we could both help to solve and then translate those insights to the clinic.”

If this holds up in the clinic, we think this approach could result in a breakthrough for small cell lung cancer patients.
Charles M. Rudin
Charles M. Rudin MSK scientist

Though not all SCLC tumors may develop resistance through this particular pathway, having a therapeutic strategy for those that do would be a big advance. Dr. Rudin likens it to the discovery of the EGFR mutation that drives a certain portion of non-small cell lung cancers — it presents a good therapeutic target, even if not everyone with NSCLC has this mutation.

“We’re really excited about this,” he says. “If this holds up in the clinic, we think this approach could result in a breakthrough for small cell lung cancer patients. It has certainly been a long time coming.”

Back to top

This work was supported by the LUNGevity Foundation, the American Lung Association, Free to Breathe, the National Institutes of Health, the Conquer Cancer Foundation of the American Society of Clinical Oncology, the Radiological Society of North America, the Department of Veterans Affairs, the Van Andel Research Institute, and Stand Up To Cancer.

Comments

This is amazing an break through for a disease that has not had further treatments in decades. Recently my dad who is a patient at Sloan was diagnosed with Stage 4 small cell.

I am hoping this breakthrough would possibly be available to him in the near future. Where does this stand as of today in the potential of treating patients? Time is of the essence for many and for many they are in dire need of better and improved treatments for small cell cancer.

Dear Matt, we recommend your father speak with his MSK team about whether this treatment may be appropriate for him. Thank you for your comment, and best wishes to you and your family.

In which clinical trials we can find treatments regarding the EZH2 which mention in this article? My mom is from Israel diagnosed with SCLC and we would like to try new way of treatments before it will be too late.

Thank you.

Dear Idan, we're sorry to hear about your mom's diagnosis. At MSK drugs that target EZH2 are currently being evaluated in trials for mesothelioma and certain types of soft-tissue sarcoma. If you are interested in finding other trials of drugs that target this mutation, you may want to go to www.clinicaltrials.gov, a database of clinical trials around the world maintained by the US National Institutes of Health. Thank you for your comment, and best wishes to you and your family.

I currently have SCLC Stage 4 I am very interesting in learning when you will start or get a approve a clinical trial on this. I was on one clinical trial, was pulled due to an allergic reaction.
Thank you

Dear Gail, we're sorry that you were unable to participate in a trial in the past. If you're interested in learning more about this research at MSK and would like to make an appointment to find out about future trials, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Thank you for your research. I am optimistic that you will find a cure for this. Thank you as well for treating my beautiful cousin Sarah. She has a long life to live and I am hopeful this is a step in the right direction.

Dear Stacia, thank you for your comment and best wishes to you and your cousin.

Hi, i have non small cell carcinoma stage 4, i am scheduled for another biopsy tomorrow at mskcc,

since i have a ret gene i have been on ret inhibitors , my question is, since im doing another biopsy and have read about chemo resistant testing, does mskcc do such a test so in case ret inhibitors will stop working and i will need to go back to chemo, would it be helpful for me to know which chem is or is not resistant for my tumor?

thank you

Dear Jehuda, we recommend that you discuss this with your MSK doctor when you come in for your biopsy. Thank you for your comment, and best wishes to you.

My husband was diagnosed with Stage 1A LSCLC in SEP of 2016 on spiral CT noting a 1.7X1.5cm nodule in left anterior lower lobe with no spread to lymph nodes or to the mediastinum. He has since been treated with Cyber-knife and 4 cycles of Platinum based chemo for which he showed a 30 % response before having PCI with Hippocampal shielding. He is due for his next round of scans in AUG (Chest CT) and SEP (Brain MRI). Would he be a candidate for this clinical trial should his cancer show new metastasis? He also has Myasthenia Gravis so I don't know if this would complicate any response to this course of treatment. Thank you and I wish success for you and your researchers in giving hope to people with this aggressive disease.

Dear Carolyn, we're sorry to hear about your husband's diagnosis. If he would like to have a consultation with an expert at MSK to find out whether he may be a candidate for a clinical trial, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you and your family.

Have you started recruiting for this clinical trial?

My husband just passed away from a rapidly progressing small cell esophageal cancer that took his life in 2 months. The cancer actually grew in the face of the first two rounds of of platinum-based chemotherapy. (He didn't survive the third round) It appears this cancer was at no point sensitive to the chemo. Question- can resistance develop PRIOR to exposure to chemo or just be resistant from the get-go? if so, does this suggest an alternative mechanism for survival of cancer cells or that this kind of cancer is a sub-category of SCC?

We're very sorry for the loss of your husband. Unfortunately, it's not possible to say why he didn't respond to the chemotherapy without being more familiar with his case. Thank you for your comment, and best wishes to you.

My husband was diagnosed in Feb is metastatic small cell. Not in brian. Lung, liver, lymph nodes. He responded well to chemo and will have ct scan in sept and last treatment was in May. In addition to conventional medicine he was treated alternatively. He is doing exceptionally well. We are anxious for results. Are there cases of 5- 10 years survivers?

Dear Barbara, we're sorry to hear about your husband's diagnosis, but we're glad to hear he's responding well to treatment. We recommend that you talk with his doctors about his prognosis. Thank you for your comment, and best wishes to you.

Is this clinical trial likely to be EZH2 given with Carboplatin and Etoposide ? My mother has had a complete response to this through 2 rounds, one lasting about 12 months before recurrence, and the second round she had a complete response lasting 6 months (from date of start of therapy) until recurrence. I would be most excited to think that Chemotherapy regimen could be effective for her again.

Dear Tara, this research is still in the very early stages. If your mother is interested in participating in a trial at MSK, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

am excited to know of your new trail for Small cell lung cancer. my question is that when the trail starts will other cancer centers have access to this trail. Am a patient @ OHSU in Portland Oregon

Dear Glen, the approach that's discussed in this article is still being evaluated in pre-clinical research and is not yet available to patients. MSK does have a number of other trials for small-cell lung cancer. You can find a list here: https://www.mskcc.org/cancer-care/clinical-trials/search?keys=&disease=…

If you are interested in participating in a trial where you live, we recommend that you discuss this with your doctors at OHSU. You may also want to go to www.clinicialtrials.gov to find out which trials may be available in your area.

Thank you for your comment, and best wishes to you.

Is there any update on this trial? I was so hopeful this may be available for my mother.

Dear Tara, we're sorry to hear about your mother's diagnosis. This trial is not yet open, but we do have other trials for small cell lung cancer. If your mother is interested in making an appointment for a consultation, she can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Add new comment

We welcome your questions and comments. While we share many of them with our world-class doctors and researchers, we regret that in order to protect your privacy, we are not able to make personal medical recommendations on this forum, nor do we publish comments that contain your personal information. If you would like to consult with an MSK doctor, we encourage you to make an appointment at 800-525-2225 or request an appointment online.

Your email address is kept private and will not be shown publicly.