Feature

New biomarkers and therapeutic target discoveries in molecular oncology

A number of significant advances in molecular oncology have come to light in recent weeks, providing new knowledge for understanding immunotherapy response, immune evasion, metastasis, radiosensitization, PARP inhibitor action and relapse of small cell lung cancer, among other areas. Here is an overview of discoveries that may be of particular interest to the clinical oncology community.

Wafik S. El-Deiry, MD, PhD, FACP
Wafik S. El-Deiry
  • Impact of the immune tumor microenvironment on tumor evolution and immune evasion — A manuscript, published in Cell by Angelova and colleagues, describes immune editing resulting in elimination or immune privilege resulting in persistence and tumor progression of cancer subclones during metastasis of colorectal cancer. The process involves a tumor escape mechanism from immune evasion from clonal immunoediting by contrast to classical acquired mutations during tumor progression. In terms of tumor recurrence risk, a high immunoscore, immunoediting and low tumor burden correlated with the lowest risk. This represents an advance in predictive science in oncology and highlights the growing complexity of mechanisms involved in tumor progression and metastasis, to be further impacted by therapeutics.
  • Tumor mutational burden, T cell-inflamed gene expression profile and PD-L1 expression are separate but complementary predictors of response to anti-PD-1 therapy — The variability of clinical responses to immune checkpoint therapy has continued to prompt scientific investigation of the underlying causes. In a study by Cristescu and colleagues published in Science, genomic analysis of more than 300 tumor samples from patients treated with pembrolizumab (Keytruda, Merck) in four KEYNOTE clinical trials revealed biomarker-defined clinical response groups based on the tumor mutational burden (TMB) and T cell-inflamed gene expression profile (GEP). The strongest responses to immunotherapy were found in the patients with GEP- and TMB-high tumors. The study delved deeper using The Cancer Genome Atlas and analyzed aspects of the tumor microenvironment within GEP-high tumors to identify TMB subgroups with associated proliferation, stroma, myeloid and vascular biology features.
  • Molecular basis of evasion of immunotherapy by Merkel cell tumors — Paulson and colleagues used single cell molecular profiling in a study published in Nature Communications to analyze Merkel cell tumor cells and other cells in the tumor microenvironment from patients treated with combination immunotherapy whose disease subsequently recurred. The insight from the single cell sequencing was that the tumor cells suppressed specific class I HLA genes, thereby making the tumor cells essentially invisible to the T cells. As this is an acquired, potentially reversible resistance mechanism, the insights are useful for potential design of more effective immunotherapy.
  • Cancer testis antigen 45 is a prognostic biomarker in ovarian cancer — Another novel discovery published in Cell by Coscia and colleagues identified cancer testis antigen 45 (CT45) as a biomarker that can predict response to therapy in ovarian cancer. Ovarian tumor cells were more likely to undergo DNA damage after exposure to carboplatin, and patients with high levels of CT45 in their tumors lived more than seven times as long as patients who had low levels of the protein. CT45 was found to be an independent prognostic factor whose expression was associated with a doubling of DFS in advanced high-grade serous ovarian cancer.
  • ctDNA as a diagnostic and monitoring tool for immunotherapy — The power of the less-invasive ctDNA utility continues to unravel, and this is summarized in an excellent review by Cabel and colleagues in Nature Reviews Clinical Oncology that focuses on immunotherapy. Not only can ctDNA help determine mismatch repair deficiency, tumor mutational burden in advanced disease, or residual tumor after therapy, but also it can be used to assess therapeutic efficacy, monitor tumor burden longitudinally, help differentiate between true and pseudoprogression of the cancer after immune checkpoint therapy, and uncover therapy-related resistance mutations.
  • Nuclear pores as a potential target in cancer therapy — Insights into the function of nuclear pores came to light in new research by McCloskey and colleagues in Genes and Development showing that cancer cells have increased numbers of nuclear pores and, surprisingly, knockdown of nucleoporin Tpr led to a high increase in the number of the nuclear pore complexes. Nuclear pores transport cargo in and out of the nucleus and are also used to export chemotherapy out of the nucleus. Tpr serves as a scaffold for ERK to phosphorylate the nucleoporin Nup153, which is critical for early stages of nuclear pore complex biogenesis. Although these findings are still far from clinical translation, they do point to a nonclassical target for therapy development.
  • Fusion hybrids of cancer cells with macrophages as predictors of patient outcomes — Fusion hybrids involving fusions between tumor cells and immune cells such as macrophages have been known for a long time. A study by Powell and colleagues, published in Cancer Research, found that tumor cells acquired properties of macrophages in the fusion hybrids to promote tumor progression, and fusion hybrids were characterized as predictors of patient outcomes. The fusion cells retain transcriptomes of the parental cells while having their own unique transcripts and provide a way for tumor cells to migrate and evade the immune system.
  • Pseudokinase TRIB2, a zombie enzyme, promotes drug resistance and can be targeted for degradation by EGFR inhibitor afatinib — The focus of the study by Foulkes and colleagues in Science Signaling is on drug repurposing such that a covalent EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim) could be used to target a mechanism of cancer therapy resistance. Pseudokinases, also known as zombie proteins, are structurally similar to kinases but lack catalytic activity. Destabilization of TRIB2 occurred in afatinib-treated acute myeloid leukemia cells and represents an off-target of the drug that may be exploited in drug repurposing.
  • Suppressing homologous recombination in radiosensitization — Glycolytic enzyme PFKFB3, which is overexpressed in cancer cells, has been identified as a critical factor in homologous recombination-mediated repair of DNA double-strand breaks. The protein localizes to foci of damage and repair and helps recruit other proteins involved in homologous recombination. In a study by Gustafsson and colleagues in Nature Communications, a small molecule pharmacological inhibitor, KAN0438757 (Kancera), was shown to target PFKFB3 and promote radiosensitization of transformed cells while not affecting normal cells.
  • Papaverine as a radiosensitizer of hypoxic tumors — Preclinical studies by Benej and colleagues in Proceedings of the National Academy of Sciences of the United States of America revealed that an old drug, papaverine, can be used to sensitize hypoxic tumor cells to radiation. The drug reduces oxygen consumption and mitochondrial complex I function of tumor cells and increases tumor oxygenation and sensitivity to radiation while normal tissue is not sensitized.
  • Methylation of one or both alleles of BRCA1 determines response to PARP inhibition — In a study published in Nature Communications providing insight into ovarian cancer responses to PARP inhibitors such as rucaparib (Rubraca, Clovis Oncology), Kondrashova and colleagues made an important advance by recognizing that methylation of one or both copies of BRCA1 in the tumor cells impacts the drug response. Heterozygous BRCA1 methylation was associated with resistance, while methylation of both copies was associated with sensitivity to the PARP inhibitor.
  • WNT pathway alterations and relapse of small cell lung cancer — Oncologists are well aware of the almost universal relapse of previously treated small cell lung cancer, although there has been little insight into the molecular mechanisms. By using whole exome sequencing of primary tumors and specimens at the time of relapse, Wagner and colleagues, in a study published in Nature Communications, found alterations in WNT signaling consistent with pathway activation as a feature of relapsed samples. This could open up strategies for therapeutic resensitization of resistant small cell lung cancer.
  • ATRX mutation increases pancreatic cancer risk in females — The novelty of this preclinical study by Young and colleagues in Cellular and Molecular Gastroenterology and Hepatology is in the identification of a sex-specific genetic risk factor for pancreatic cancer. ATRX mutations are found in females with pancreatic cancer, and the gene is X-linked. ATRX mutation increases sensitivity of pancreatic cells to injury and to the effects of KRAS mutation.
  • A more limited spectrum of PMS2 mutations in Lynch Syndrome suggests more restricted screening —PMS2 mutation carriers were at increased risk for colorectal and endometrial cancer, but not other Lynch Syndrome-associated tumors. The findings by Ten Broeke and colleagues in Journal of Clinical Oncology highlight differences in cancer risk among different mismatch repair gene defects, and also suggest more limited screening where the risk of certain malignancies with specific gene defects would be extremely rare or nonexistent.
References:

Angelova M, et al. Cell. 2018;doi:10.1016/j.cell.2018.09.018.

Benej M, et al. Proc Natl Acad Sci USA. 2018;doi:10.1073/pnas.1808945115.

Cabel L, et al. Nat Rev Clin Oncol. 2018;doi:10.1038/s41571-018-0074-3.

Coscia F, et al. Cell. 2018;doi:10.1016/j.cell.2018.08.065i.

Cristescu R, et al. Science. 2018;doi:10.1126/science/aar3593.

Foulkes DM, et al. Sci Signal. 2018;doi:10.1126/scisignal.aat7951.

Gustafsson NM, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06287-x.

Kondrashova O, et al. Nat Commun. 2018;doi:10.1038/s41467-018-05564-z.

McCloskey A, et al. Genes Devel. 2018;doi:10.1101/gad.315523.118.

Paulson KG, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06300-3.

Powell AE, et al. Cancer Res. 2018;doi:10.1158/0008-5472.CAN-10-3223.

Ten Broeke SW, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.78.4777.

Wagner AH, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06162-9.

Young CC, et al. Cell Mol Gastroenterol Hepatol. 2018;doi:10.1016/j.jcmgh.2018.09.004.

For more information:

Wafik S. El-Deiry, MD, PhD, FACP, is deputy director of Fox Chase Cancer Center and HemOnc Today’s Associate Editor for Molecular Oncology. To contribute to this column or suggest topics, email him at wafik.eldeiry@gmail.com.

Disclosure: El-Deiry reports no relevant financial disclosures.

A number of significant advances in molecular oncology have come to light in recent weeks, providing new knowledge for understanding immunotherapy response, immune evasion, metastasis, radiosensitization, PARP inhibitor action and relapse of small cell lung cancer, among other areas. Here is an overview of discoveries that may be of particular interest to the clinical oncology community.

Wafik S. El-Deiry, MD, PhD, FACP
Wafik S. El-Deiry
  • Impact of the immune tumor microenvironment on tumor evolution and immune evasion — A manuscript, published in Cell by Angelova and colleagues, describes immune editing resulting in elimination or immune privilege resulting in persistence and tumor progression of cancer subclones during metastasis of colorectal cancer. The process involves a tumor escape mechanism from immune evasion from clonal immunoediting by contrast to classical acquired mutations during tumor progression. In terms of tumor recurrence risk, a high immunoscore, immunoediting and low tumor burden correlated with the lowest risk. This represents an advance in predictive science in oncology and highlights the growing complexity of mechanisms involved in tumor progression and metastasis, to be further impacted by therapeutics.
  • Tumor mutational burden, T cell-inflamed gene expression profile and PD-L1 expression are separate but complementary predictors of response to anti-PD-1 therapy — The variability of clinical responses to immune checkpoint therapy has continued to prompt scientific investigation of the underlying causes. In a study by Cristescu and colleagues published in Science, genomic analysis of more than 300 tumor samples from patients treated with pembrolizumab (Keytruda, Merck) in four KEYNOTE clinical trials revealed biomarker-defined clinical response groups based on the tumor mutational burden (TMB) and T cell-inflamed gene expression profile (GEP). The strongest responses to immunotherapy were found in the patients with GEP- and TMB-high tumors. The study delved deeper using The Cancer Genome Atlas and analyzed aspects of the tumor microenvironment within GEP-high tumors to identify TMB subgroups with associated proliferation, stroma, myeloid and vascular biology features.
  • Molecular basis of evasion of immunotherapy by Merkel cell tumors — Paulson and colleagues used single cell molecular profiling in a study published in Nature Communications to analyze Merkel cell tumor cells and other cells in the tumor microenvironment from patients treated with combination immunotherapy whose disease subsequently recurred. The insight from the single cell sequencing was that the tumor cells suppressed specific class I HLA genes, thereby making the tumor cells essentially invisible to the T cells. As this is an acquired, potentially reversible resistance mechanism, the insights are useful for potential design of more effective immunotherapy.
  • Cancer testis antigen 45 is a prognostic biomarker in ovarian cancer — Another novel discovery published in Cell by Coscia and colleagues identified cancer testis antigen 45 (CT45) as a biomarker that can predict response to therapy in ovarian cancer. Ovarian tumor cells were more likely to undergo DNA damage after exposure to carboplatin, and patients with high levels of CT45 in their tumors lived more than seven times as long as patients who had low levels of the protein. CT45 was found to be an independent prognostic factor whose expression was associated with a doubling of DFS in advanced high-grade serous ovarian cancer.
  • ctDNA as a diagnostic and monitoring tool for immunotherapy — The power of the less-invasive ctDNA utility continues to unravel, and this is summarized in an excellent review by Cabel and colleagues in Nature Reviews Clinical Oncology that focuses on immunotherapy. Not only can ctDNA help determine mismatch repair deficiency, tumor mutational burden in advanced disease, or residual tumor after therapy, but also it can be used to assess therapeutic efficacy, monitor tumor burden longitudinally, help differentiate between true and pseudoprogression of the cancer after immune checkpoint therapy, and uncover therapy-related resistance mutations.
  • Nuclear pores as a potential target in cancer therapy — Insights into the function of nuclear pores came to light in new research by McCloskey and colleagues in Genes and Development showing that cancer cells have increased numbers of nuclear pores and, surprisingly, knockdown of nucleoporin Tpr led to a high increase in the number of the nuclear pore complexes. Nuclear pores transport cargo in and out of the nucleus and are also used to export chemotherapy out of the nucleus. Tpr serves as a scaffold for ERK to phosphorylate the nucleoporin Nup153, which is critical for early stages of nuclear pore complex biogenesis. Although these findings are still far from clinical translation, they do point to a nonclassical target for therapy development.
  • Fusion hybrids of cancer cells with macrophages as predictors of patient outcomes — Fusion hybrids involving fusions between tumor cells and immune cells such as macrophages have been known for a long time. A study by Powell and colleagues, published in Cancer Research, found that tumor cells acquired properties of macrophages in the fusion hybrids to promote tumor progression, and fusion hybrids were characterized as predictors of patient outcomes. The fusion cells retain transcriptomes of the parental cells while having their own unique transcripts and provide a way for tumor cells to migrate and evade the immune system.
  • Pseudokinase TRIB2, a zombie enzyme, promotes drug resistance and can be targeted for degradation by EGFR inhibitor afatinib — The focus of the study by Foulkes and colleagues in Science Signaling is on drug repurposing such that a covalent EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim) could be used to target a mechanism of cancer therapy resistance. Pseudokinases, also known as zombie proteins, are structurally similar to kinases but lack catalytic activity. Destabilization of TRIB2 occurred in afatinib-treated acute myeloid leukemia cells and represents an off-target of the drug that may be exploited in drug repurposing.
  • Suppressing homologous recombination in radiosensitization — Glycolytic enzyme PFKFB3, which is overexpressed in cancer cells, has been identified as a critical factor in homologous recombination-mediated repair of DNA double-strand breaks. The protein localizes to foci of damage and repair and helps recruit other proteins involved in homologous recombination. In a study by Gustafsson and colleagues in Nature Communications, a small molecule pharmacological inhibitor, KAN0438757 (Kancera), was shown to target PFKFB3 and promote radiosensitization of transformed cells while not affecting normal cells.
  • Papaverine as a radiosensitizer of hypoxic tumors — Preclinical studies by Benej and colleagues in Proceedings of the National Academy of Sciences of the United States of America revealed that an old drug, papaverine, can be used to sensitize hypoxic tumor cells to radiation. The drug reduces oxygen consumption and mitochondrial complex I function of tumor cells and increases tumor oxygenation and sensitivity to radiation while normal tissue is not sensitized.
  • Methylation of one or both alleles of BRCA1 determines response to PARP inhibition — In a study published in Nature Communications providing insight into ovarian cancer responses to PARP inhibitors such as rucaparib (Rubraca, Clovis Oncology), Kondrashova and colleagues made an important advance by recognizing that methylation of one or both copies of BRCA1 in the tumor cells impacts the drug response. Heterozygous BRCA1 methylation was associated with resistance, while methylation of both copies was associated with sensitivity to the PARP inhibitor.
  • WNT pathway alterations and relapse of small cell lung cancer — Oncologists are well aware of the almost universal relapse of previously treated small cell lung cancer, although there has been little insight into the molecular mechanisms. By using whole exome sequencing of primary tumors and specimens at the time of relapse, Wagner and colleagues, in a study published in Nature Communications, found alterations in WNT signaling consistent with pathway activation as a feature of relapsed samples. This could open up strategies for therapeutic resensitization of resistant small cell lung cancer.
  • ATRX mutation increases pancreatic cancer risk in females — The novelty of this preclinical study by Young and colleagues in Cellular and Molecular Gastroenterology and Hepatology is in the identification of a sex-specific genetic risk factor for pancreatic cancer. ATRX mutations are found in females with pancreatic cancer, and the gene is X-linked. ATRX mutation increases sensitivity of pancreatic cells to injury and to the effects of KRAS mutation.
  • A more limited spectrum of PMS2 mutations in Lynch Syndrome suggests more restricted screening —PMS2 mutation carriers were at increased risk for colorectal and endometrial cancer, but not other Lynch Syndrome-associated tumors. The findings by Ten Broeke and colleagues in Journal of Clinical Oncology highlight differences in cancer risk among different mismatch repair gene defects, and also suggest more limited screening where the risk of certain malignancies with specific gene defects would be extremely rare or nonexistent.
References:

Angelova M, et al. Cell. 2018;doi:10.1016/j.cell.2018.09.018.

Benej M, et al. Proc Natl Acad Sci USA. 2018;doi:10.1073/pnas.1808945115.

Cabel L, et al. Nat Rev Clin Oncol. 2018;doi:10.1038/s41571-018-0074-3.

Coscia F, et al. Cell. 2018;doi:10.1016/j.cell.2018.08.065i.

Cristescu R, et al. Science. 2018;doi:10.1126/science/aar3593.

Foulkes DM, et al. Sci Signal. 2018;doi:10.1126/scisignal.aat7951.

Gustafsson NM, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06287-x.

Kondrashova O, et al. Nat Commun. 2018;doi:10.1038/s41467-018-05564-z.

McCloskey A, et al. Genes Devel. 2018;doi:10.1101/gad.315523.118.

Paulson KG, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06300-3.

Powell AE, et al. Cancer Res. 2018;doi:10.1158/0008-5472.CAN-10-3223.

Ten Broeke SW, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.78.4777.

Wagner AH, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06162-9.

Young CC, et al. Cell Mol Gastroenterol Hepatol. 2018;doi:10.1016/j.jcmgh.2018.09.004.

For more information:

Wafik S. El-Deiry, MD, PhD, FACP, is deputy director of Fox Chase Cancer Center and HemOnc Today’s Associate Editor for Molecular Oncology. To contribute to this column or suggest topics, email him at wafik.eldeiry@gmail.com.

Disclosure: El-Deiry reports no relevant financial disclosures.