Precision treatment

SLFN11 biomarker will help predict the effectiveness of cancer therapies

Wroclaw Medical University

A new treatment unveiling

Imagine doctors being able to tailor cancer therapy to the type of tumor, knowing which drugs will work best and which should be avoided. Does this sound like the medicine of the future? Thanks to research on a biomarker called SLFN11, personalization of treatment is becoming increasingly feasible.

 

A team of scientists led by Dr. Maciej Kaczorowski of the Department of Clinical and Experimental Pathology at the Wroclaw Medical University has published the results of their research in the pages of "The American Journal of Surgical Pathology". The article titled "Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets" describes an analysis of more than 6,600 samples from 127 different tumor types. The results indicate that the level of SLFN11 protein expression in cancer cells can help identify cancers that will potentially respond best to therapies targeting SLFN11-dependent mechanisms.

What is the SLFN11 biomarker?

SLFN11 (Schlafen 11) is a protein that plays a key role in the cell's response to replication stress. When a cell's DNA becomes damaged—which is the target of many cancer drugs—the presence of SLFN11 can block the DNA replication process, ultimately leading to cancer cell death.

This function makes SLFN11 a biomarker of great clinical importance. Its presence in a tumor may indicate that cancer cells are more susceptible to therapies based on DNA damage.

"Tumors in which SLFN11 expression is found are more sensitive to DNA-damaging drugs and DNA repair blockers, such as PARP inhibitors. The prospect lies ahead of us, in which a patient with cancer characterized by SLFN11 expression will receive personalized treatment that takes advantage of this particular sensitivity of his disease to certain drugs", explains Dr. Maciej Kaczorowski, an author of the study.

Dr. Maciej Kaczorowski, Department of Clinical and Experimental Pathology at the Wroclaw Medical University, an author of the study (Photo by Tomasz Walów.)

Dr. Maciej Kaczorowski, Department of Clinical and Experimental Pathology at the Wroclaw Medical University, an author of the study Fot. Tomasz Walów.

This is why the SLFN11 protein could become essential in personalizing cancer treatment. Instead of using a single therapy regimen for all patients, doctors could more precisely select drugs for each patient based on analysis of SLFN11 expression. For patients, this means a better chance of a cure and avoiding unnecessary toxicity from drugs that may not be as effective as currently assumed.

SLFN11 under the magnifying glass

One method for detecting SLFN11 in tumor tissues is immunohistochemistry (IHC), which allows the protein to be detected directly in tumor cells. In practice, this means using antibodies that bind to the SLFN11 protein in the diseased tissue sample under investigation. Stains are then used to reveal the presence of the biomarker in the form of coloured? areas visible under the microscope. This allows the pathologist to not only detect the presence of the protein but also to determine which cells in the tumor are producing it.

"Immunohistochemistry appears to be the best method for assessing SLFN11 expression. It allows us to analyze the presence of this biomarker in correlation with the morphology of the tissue, which gives confidence that it is indeed the tumor cells that are expressing SLFN11", explains Dr. Kaczorowski.

An alternative to immunohistochemistry is testing the level of mRNA encoding SLFN11, which is based on techniques such as RT-PCR. While this method is highly sensitive and can detect the presence of mRNA, it has a significant drawback - it does not distinguish whether the mRNA comes from tumor cells or cells surrounding the tumor.

- The result can be flawed, false positive, by the widespread presence of SLFN11 in cells of the tumor microenvironment, such as stromal fibroblasts or lymphocytes, Dr. Kaczorowski explains.

This makes IHC a more precise and practical method, especially if it is to be used in clinical diagnostics. An additional advantage of immunohistochemistry is that it allows the assessment on the protein level, not just its mRNA, which closer reflects the biological activity of SLFN11 in cells. When mRNA is evaluated, even if its level is high, it only sometimes means that the protein is present sufficiently to exert biological effects. As a result, immunohistochemistry is considered the "gold standard" for evaluating protein biomarkers in oncology.

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When does the presence of SLFN11 matter?

In the study presented in the article, the team analyzed 6658 tumor samples representing 127 different cancer types. The samples were divided into groups according to the level of SLFN11 expression: high-expressing tumors, which may respond better to DNA-damaging drugs, and low-expressing tumors, which are less sensitive to these therapies.

Tumors with high SLFN11 expression

This group included cancers in which a majority of samples showed the presence of SLFN11. In some cases, the biomarker was present in almost all tumor cells. These tumors may be good candidates for treatment with DNA-damaging drugs.

Mesenchymal and Neuroectodermal Tumors:

  • Desmoplastic Small Round Cell Tumor (DSRCT)
  • Ewing Sarcoma
  • Undifferentiated Sarcoma
  • Synovial Sarcoma
  • Malignant Peripheral Nerve Sheath Tumor (MPNST)
  • Solitary Fibrous Tumor (SFT)
  • Dedifferentiated Liposarcoma (DDLPS)

Epithelial Tumors:

  • Pleural Mesothelioma
  • Clear Cell Renal Cell Carcinoma
  • Small Cell Lung Cancer
  • Squamous Cell Carcinoma of the Tonsil
  • Laryngeal Squamous Cell Carcinoma
  • Ovarian Serous Carcinoma

The high expression of SLFN11 in tumors in this group means that the cancer cells may be more susceptible to PARP inhibitors, alkylating drugs, or other therapies based on DNA damage. In some cases, such as Ewing sarcoma and DSRCT tumors, almost all samples showed the presence of SLFN11, suggesting that these may be some of the best candidates for DNA-targeting therapies.

Tumors with low SLFN11 expression

This group included tumors in which SLFN11 expression was detected much less frequently—often in less than 10% of samples. These types of tumors may be more resistant to DNA-damaging therapies because their tumor cells can repair the resulting damage without activating a self-destruct mechanism.

Epithelial Tumors:

  • Hepatocellular Carcinoma (HCC)
  • Prostate Cancer
  • Colorectal Cancer
  • Breast Cancer
  • Chromophobe Renal Cell Carcinoma
  • Neuroendocrine Tumors of the Pancreas, Intestines, and Stomach
  • Medullary Thyroid Carcinoma

Low or absent expression of SLFN11 in these tumors suggests that DNA-damaging drugs may be less effective.

Strategies for SLFN11 activation in resistant cancers

Researchers seek alternative therapeutic strategies for patients whose tumors do not express SLFN11.

"Modulation of epigenetic processes can increase SLFN11 levels in tumor cells. Such strategies are currently being tested with good results in preclinical studies", Dr. Kaczorowski explains.

The epigenetic approach involves modifying the “chemical environment” of the tumor genome, which determines which genes are active and which are silenced. This uses inhibitors of histone deacetylases (HDACi) and inhibitors of DNA methyltransferases (e.g., decitabine), which can restore SLFN11 expression. Deacetylation and methylation are processes that "silence" genes and epigenetic drugs aim to reverse this silencing. Although studies in cell lines and animal models show promising results, the challenges associated with the toxicity of such drugs remain a significant barrier. This is because they act not only on cancer cells but also on healthy cells in the body, which can lead to side effects such as lowered blood cell counts and liver damage.

Another solution currently being tested is to circumvent the lack of SLFN11 by attacking other molecular pathways that regulate the cellular response to DNA damage.

- The use of inhibitors of WEE1, CHK1 and ATR proteins increases susceptibility to DNA-damaging drugs even in cells that lack SLFN11, Dr. Kaczorowski explains.

The inhibitors target proteins that regulate the cell cycle and DNA repair. Blocking these proteins causes cancer cells to lose their ability to repair DNA properly, making them more susceptible to drugs that damage genetic material. This approach aims to “force” the death of cancer cells, even if they do not produce SLFN11.

Although these strategies are still preclinical, their potential is significant.

- While targeted treatments for SLFN11-expressing cancers seem to be on the horizon, strategies to activate SLFN11 in cancer cells will have to wait, Dr. Kaczorowski admits.

Research on SLFN11-activating drugs is ongoing, and developing effective methods could expand treatment options for patients with tumors resistant to standard DNA damage-based therapies. If these methods are refined, doctors will have a broader range of therapeutic options, and patients will have a better chance of successful treatment.

Standardization of tests for SLFN11

Although immunohistochemistry is the most effective method for assessing SLFN11, it needs to be standardized for use in daily clinical practice.

"Undoubtedly, standardization of the method for determining SLFN11 in tumor tissue is essential if this test is to become part of routine diagnostics and oncological treatment planning", says Dr. Kaczorowski.

The researcher explains that the optimal clone of the SLFN11-detecting antibody, the immunohistochemical reaction protocol, and the hardware platform must be standardized. Similar standards are already in place for tests assessing HER2 expression in breast cancer or PD-L1 for cancer immunotherapy.

Research by Dr. Maciej Kaczorowski's team shows that SLFN11 could become an important biomarker in cancer treatment. Although targeted therapy of SLFN11-expressing cancers is getting closer in everyday clinical life, studies are still needed to evaluate the effectiveness of SLFN11 activation strategies in refractory cancers.

As Dr. Kaczorowski concludes, "Our results provide a signpost for future clinical trials, showing which cancers are promising candidates for planning therapies based on SLFN11 expression."

If these efforts bear fruit, SLFN11 will be one of the essential pieces of the personalized oncology puzzle. For patients, this means more than just another biomarker - it's a chance for treatments that don't rely on drugs that are ineffective in some cases. In practice, this can translate into shorter hospitalizations and, most importantly, hope for a longer and better life. For many patients, a cancer diagnosis is not just a question of "Are there drugs?" but "Will these drugs work on my tumor?". The biomarker SLFN11 may provide the answer.

D. Sikora

FAQ: SLFN11 expression in cancer

What is SLFN11, and why is it important in cancer treatment?

Schlafen 11 (SLFN11) is a protein that plays a key role in the body's response to DNA damage, especially that caused by specific cancer therapies. It acts as a regulator of the cellular response to replicative stress. Its presence in cancer cells can increase their sensitivity to DNA-damaging chemotherapeutics and PARP inhibitors. This makes SLFN11 expression a potentially valuable biomarker for predicting how well a patient might respond to these therapies.

What happens if a tumor lacks SLFN11 expression?

Tumors lacking SLFN11 may be resistant to DNA-damaging chemotherapies and PARP inhibitors. If the tumor is found to be SLFN11-negative, alternative treatments may be necessary.

What are the next steps in the research and clinical application of SLFN11?

Further research is needed to:

  • Standardize SLFN11 testing methodologies to ensure accurate and reliable results.
  • Determine the clinical significance of different levels of SLFN11 expression.
  • Conduct clinical trials to confirm the predictive value of SLFN11 expression for specific therapies.

Investigate and refine strategies to overcome SLFN11 deficiency and improve treatment outcomes.

How is SLFN11 expression measured in tumors?

The most effective way to measure SLFN11 expression in tumor cells is through immunohistochemical (IHC) staining of tumor samples. This method uses antibodies to detect the presence and localization of SLFN11 protein in cells. Although molecular genetic testing of SLFN11 mRNA is possible, it is less accurate because it detects SLFN11 expression in surrounding non-cancerous cells, leading to false positives.

 

Are there ways to overcome SLFN11 deficiency and improve response to treatment?

Research is ongoing on ways to overcome SLFN11 deficiency and sensitize resistant tumors to treatment. Some potential strategies include:

  • Increasing SLFN11 expression with drugs such as histone deacetylase inhibitors or EZH2 inhibitors.
  • Gene editing techniques, such as CRISPR/dCas9, activate SLFN11.
  • Combining DNA-damaging agents with inhibitors of specific cell cycle regulators to bypass the need for SLFN11.

The material is based on the article:

Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets

Maciej Kaczorowski, Kris Ylaya, Małgorzata Chłopek, Daiki Taniyama, Yves Pommier, Jerzy Lasota, Markku Miettinen

The American Journal of Surgical Pathology

doi: 10.1097/PAS.0000000000002299

Web. A. Hasiak

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