Feature

Recent advances push forward the field of molecular oncology

A number of recent advances in molecular oncology are noteworthy for our new regular column, which launched in September.

Here is an overview of those developments and their potential impacts.

  • BRCA1 gene variants unraveled — An important advance reported by Findlay and colleagues in Nature involves progress in unraveling the functional consequences of nearly 4,000 variants of unknown significance in the BRCA1 gene.
Wafik S. El-Deiry, MD, PhD, FACP
Wafik S. El-Deiry

Mutations in the BRCA1 gene confer a high lifetime risk for breast or ovarian cancers. Approximately 72% of women with inherited BRCA1 mutations will develop breast cancer by age 80 years.

Although the functional consequences of many mutated BRCA1 alleles are known, in the clinic some sequence alterations have simply not been characterized and were not known to be associated with increased risk for disease and potential sensitivity to PARP inhibitors.

Findlay and colleagues identified more than 400 nonfunctional missense BRCA1 sequence variants, and approximately 300 variants were found to disrupt BRCA1 expression.

This new knowledge has immediate clinical relevance in the world of clinical genetics and precision oncology, as now all patients whose tumors or germline harbor pathogenic variants can be directed toward appropriate counseling and therapy.

  • BRCA1-associated protein as tumor suppressor through ferroptosis — We have known about BRCA1-associated protein (BAP1) for several years as a gene that can be mutated in mesothelioma and uveal melanoma.

However, in a study published in Nature Cell Biology, Zhang and colleagues report that the tumor suppressor BAP1 — which encodes a nuclear deubiquitinating enzyme — impacts on a cysteine transporter (SLC7A11) through epigenetic repression of its expression.

Inhibition of SLC7A11 reduces cysteine uptake, which increases lipid peroxidation and ferroptosis in tumor cells.

Ferroptosis — a form of programmed cell death discovered in 2012 — plays a significant role in cancer suppression through lipid peroxidation. Several drugs, including sorafenib and erastin, can induce ferroptosis.

  • Natural killer cells play role in cancer immune therapy, vaccination and T-cell metabolism — New insights into the efficacy of immune checkpoint blockade came from a study by Hsu and colleagues. The study, published in Journal of Clinical Investigation, implicated natural killer (NK) cells.

It is clear that NK cells express PD-1 and that tumor cell PD-L1 can inhibit their antitumor effects. PD-L1 can inhibit not only cytotoxic T-cell activity, but also NK-cell cytotoxicity toward tumor cells.

This study not only implicates a role for NK cells in immune checkpoint therapy, but also makes suggestions for potentially novel therapy combinations involving NK cells and T cells to enhance immune checkpoint blockade in cancer therapy.

In other developments, there is increasing effort to develop chimeric antigen receptor-NK cells as novel cellular therapies for cancer.

Another novel approach, published in Proceedings of the National Academy of Sciences of the United States of America, involves preclinical use of Diprovocim (Tollbridge Therapeutics), a TLR1/TLR2 agonist, to synergize with anti-PD-L1 against melanoma. This vaccination approach helps recruit immune cells to tumors.

In this regard, a basic insight published in Science Immunology that T cells elicited from vaccines do not depend on aerobic glycolysis has implications for cancer immunotherapy, as both cancer cells and immune cells can end up competing for glucose in the tumor microenvironment.

  • Understanding why some microsatellite stable tumors respond to immunotherapy — Although we know that tumors with microsatellite instability have a high response rate to immune checkpoint blockade therapy, many patients do not have the mismatch repair defect or high tumor mutation burden and, therefore, do not benefit.

This is especially true when more than 95% of patients with metastatic colorectal cancer are mismatch repair proficient and, therefore, not generally responsive to immune checkpoint blockage therapy.

In a paper published in Nature Genetics, Miao and colleagues not only confirmed that tumor mutation burden matters for response to immune checkpoint blockade therapy in microsatellite stable tumors, but that other factors impact the response.

Researchers showed that KRAS and PIK3CA mutations were enriched in responders, whereas EGFR mutation was enriched in nonresponders. Patients with tumors harboring an APOBEC signature or PBRM1 mutation also were among the responders to immune checkpoint blockade therapy.

These studies add insights to at least help understand patterns of response to immune checkpoint blockade therapy and, perhaps at some point, impact toward directing patients who are predicted to respond to appropriate clinical trials.

  • Driver gene mutations common to different metastases of untreated tumors — Tumor evolution and heterogeneity in the face of anticancer therapy present formidable challenges to disease control and prolongation of life.

There is an expanding literature — fueled by the emergence and clinical use of liquid biopsy technology coupled with detailed tumor tissue analysis — that suggests subclonal evolution within metastasis leading to multiple mechanisms of drug resistance in a given patient (eg, to cetuximab [Erbitux, Eli Lilly] in colorectal cancer).

On the other hand — and this remains not well known in oncology — there is increasing evidence that treatment-naive tumors harbor little heterogeneity in metastatic lesions.

Makohon-Moore and colleagues reported this last year in Nature Genetics in a study focused on pancreatic cancer, and now in several other tumor types in a paper published in Science.

These reports support the understanding that tumor metastases are more similar to primary tumors in terms of driver gene mutations than what might be expected. It is important to understand that these findings apply to untreated tumors where a biopsy from a metastasis may be helpful for therapy planning, as is analysis of the primary tumor.

For patients who have undergone therapy for metastatic cancer, there is clearly tumor evolution that can be divergent among metastases. Russo and colleagues showed this for colorectal cancer in a paper published in Cancer Discovery.

Thus, for patients who have metastatic cancer and were previously treated, it is not clear that analysis of a single metastasis would suffice. This is an area where complementary information from a liquid biopsy may be valuable.

  • Epigenetic heterogeneity in glioblastoma — Glioblastoma remains a deadly tumor in need of more understanding in terms of molecular pathogenesis and progression Novel therapies also are needed.

In a study published in Nature Medicine, Klughammer and colleagues investigated DNA methylation patterns in matched normal and glioblastoma tumors. Researchers identified changes in recurrent tumors, as well as impact of the tumor microenvironment.

The findings have impact on prognostication and speak to the complexity and enormous challenge of dealing with glioblastoma tumors.

  • Arsenic and retinoic acid converge to inhibit Pin1 for breast and other cancers — Pin1 is a protein kinase, like Akt, that may be a major target for cancer therapy development.

In a study published in Nature Communications, Kozono and colleagues reported that both arsenic and retinoic acid can inhibit a cancer-driving pathway controlled by Pin1, and this included inhibition of tumor-initiating cancer stem cells.

Because Pin1 is overexpressed in multiple cancer types such as breast cancer, prostate cancer and other malignancies, the findings present a novel strategy for therapy development.

References:

Findlay GM, et al. Nature. 2018;doi:10.1038/s41586-018-0461-z.

Hsu J, et al. J Clin Invest. 2018;doi:10.1172/JCI99317.

Klarquist J, et al. Sci Immunol. 2018;doi:10.1126/sciimmunol.aas9822.

Kozono S, et al. Nat Commun. 2018;doi:10.1038/s41467-018-05402-2.

Kuchenbaecker KB, et al. JAMA. 2017;doi:10.1001/jama.2017.7112.

Leslie M. Science. 2018; doi:10.1126/science.aav4154.

Makohon-Moore AP, et al. Nat Genet. 2017;doi:10.1038/ng.3764.

Miao D, et al. Nat Genet. 2018;doi:10.1038/s41588-018-0200-2.

Reiter JG, et al. Science. 2018;doi:10.1126/science.aat7171.

Russo M, et al. Cancer Discov. 2016;doi:10.1158/2159-8290.CD-15-1283.

Wang Y, et al. Proc Natl Acad Sci USA. 2018;doi:10.1073/pnas.1809232115.

Zhang Y, et al. Nat Cell Biol. 2018;doi:10.1038/s41556-018-0178-0.

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 recent advances in molecular oncology are noteworthy for our new regular column, which launched in September.

Here is an overview of those developments and their potential impacts.

  • BRCA1 gene variants unraveled — An important advance reported by Findlay and colleagues in Nature involves progress in unraveling the functional consequences of nearly 4,000 variants of unknown significance in the BRCA1 gene.
Wafik S. El-Deiry, MD, PhD, FACP
Wafik S. El-Deiry

Mutations in the BRCA1 gene confer a high lifetime risk for breast or ovarian cancers. Approximately 72% of women with inherited BRCA1 mutations will develop breast cancer by age 80 years.

Although the functional consequences of many mutated BRCA1 alleles are known, in the clinic some sequence alterations have simply not been characterized and were not known to be associated with increased risk for disease and potential sensitivity to PARP inhibitors.

Findlay and colleagues identified more than 400 nonfunctional missense BRCA1 sequence variants, and approximately 300 variants were found to disrupt BRCA1 expression.

This new knowledge has immediate clinical relevance in the world of clinical genetics and precision oncology, as now all patients whose tumors or germline harbor pathogenic variants can be directed toward appropriate counseling and therapy.

  • BRCA1-associated protein as tumor suppressor through ferroptosis — We have known about BRCA1-associated protein (BAP1) for several years as a gene that can be mutated in mesothelioma and uveal melanoma.

However, in a study published in Nature Cell Biology, Zhang and colleagues report that the tumor suppressor BAP1 — which encodes a nuclear deubiquitinating enzyme — impacts on a cysteine transporter (SLC7A11) through epigenetic repression of its expression.

Inhibition of SLC7A11 reduces cysteine uptake, which increases lipid peroxidation and ferroptosis in tumor cells.

Ferroptosis — a form of programmed cell death discovered in 2012 — plays a significant role in cancer suppression through lipid peroxidation. Several drugs, including sorafenib and erastin, can induce ferroptosis.

  • Natural killer cells play role in cancer immune therapy, vaccination and T-cell metabolism — New insights into the efficacy of immune checkpoint blockade came from a study by Hsu and colleagues. The study, published in Journal of Clinical Investigation, implicated natural killer (NK) cells.

It is clear that NK cells express PD-1 and that tumor cell PD-L1 can inhibit their antitumor effects. PD-L1 can inhibit not only cytotoxic T-cell activity, but also NK-cell cytotoxicity toward tumor cells.

This study not only implicates a role for NK cells in immune checkpoint therapy, but also makes suggestions for potentially novel therapy combinations involving NK cells and T cells to enhance immune checkpoint blockade in cancer therapy.

PAGE BREAK

In other developments, there is increasing effort to develop chimeric antigen receptor-NK cells as novel cellular therapies for cancer.

Another novel approach, published in Proceedings of the National Academy of Sciences of the United States of America, involves preclinical use of Diprovocim (Tollbridge Therapeutics), a TLR1/TLR2 agonist, to synergize with anti-PD-L1 against melanoma. This vaccination approach helps recruit immune cells to tumors.

In this regard, a basic insight published in Science Immunology that T cells elicited from vaccines do not depend on aerobic glycolysis has implications for cancer immunotherapy, as both cancer cells and immune cells can end up competing for glucose in the tumor microenvironment.

  • Understanding why some microsatellite stable tumors respond to immunotherapy — Although we know that tumors with microsatellite instability have a high response rate to immune checkpoint blockade therapy, many patients do not have the mismatch repair defect or high tumor mutation burden and, therefore, do not benefit.

This is especially true when more than 95% of patients with metastatic colorectal cancer are mismatch repair proficient and, therefore, not generally responsive to immune checkpoint blockage therapy.

In a paper published in Nature Genetics, Miao and colleagues not only confirmed that tumor mutation burden matters for response to immune checkpoint blockade therapy in microsatellite stable tumors, but that other factors impact the response.

Researchers showed that KRAS and PIK3CA mutations were enriched in responders, whereas EGFR mutation was enriched in nonresponders. Patients with tumors harboring an APOBEC signature or PBRM1 mutation also were among the responders to immune checkpoint blockade therapy.

These studies add insights to at least help understand patterns of response to immune checkpoint blockade therapy and, perhaps at some point, impact toward directing patients who are predicted to respond to appropriate clinical trials.

  • Driver gene mutations common to different metastases of untreated tumors — Tumor evolution and heterogeneity in the face of anticancer therapy present formidable challenges to disease control and prolongation of life.

There is an expanding literature — fueled by the emergence and clinical use of liquid biopsy technology coupled with detailed tumor tissue analysis — that suggests subclonal evolution within metastasis leading to multiple mechanisms of drug resistance in a given patient (eg, to cetuximab [Erbitux, Eli Lilly] in colorectal cancer).

On the other hand — and this remains not well known in oncology — there is increasing evidence that treatment-naive tumors harbor little heterogeneity in metastatic lesions.

Makohon-Moore and colleagues reported this last year in Nature Genetics in a study focused on pancreatic cancer, and now in several other tumor types in a paper published in Science.

PAGE BREAK

These reports support the understanding that tumor metastases are more similar to primary tumors in terms of driver gene mutations than what might be expected. It is important to understand that these findings apply to untreated tumors where a biopsy from a metastasis may be helpful for therapy planning, as is analysis of the primary tumor.

For patients who have undergone therapy for metastatic cancer, there is clearly tumor evolution that can be divergent among metastases. Russo and colleagues showed this for colorectal cancer in a paper published in Cancer Discovery.

Thus, for patients who have metastatic cancer and were previously treated, it is not clear that analysis of a single metastasis would suffice. This is an area where complementary information from a liquid biopsy may be valuable.

  • Epigenetic heterogeneity in glioblastoma — Glioblastoma remains a deadly tumor in need of more understanding in terms of molecular pathogenesis and progression Novel therapies also are needed.

In a study published in Nature Medicine, Klughammer and colleagues investigated DNA methylation patterns in matched normal and glioblastoma tumors. Researchers identified changes in recurrent tumors, as well as impact of the tumor microenvironment.

The findings have impact on prognostication and speak to the complexity and enormous challenge of dealing with glioblastoma tumors.

  • Arsenic and retinoic acid converge to inhibit Pin1 for breast and other cancers — Pin1 is a protein kinase, like Akt, that may be a major target for cancer therapy development.

In a study published in Nature Communications, Kozono and colleagues reported that both arsenic and retinoic acid can inhibit a cancer-driving pathway controlled by Pin1, and this included inhibition of tumor-initiating cancer stem cells.

Because Pin1 is overexpressed in multiple cancer types such as breast cancer, prostate cancer and other malignancies, the findings present a novel strategy for therapy development.

References:

Findlay GM, et al. Nature. 2018;doi:10.1038/s41586-018-0461-z.

Hsu J, et al. J Clin Invest. 2018;doi:10.1172/JCI99317.

Klarquist J, et al. Sci Immunol. 2018;doi:10.1126/sciimmunol.aas9822.

Kozono S, et al. Nat Commun. 2018;doi:10.1038/s41467-018-05402-2.

Kuchenbaecker KB, et al. JAMA. 2017;doi:10.1001/jama.2017.7112.

Leslie M. Science. 2018; doi:10.1126/science.aav4154.

Makohon-Moore AP, et al. Nat Genet. 2017;doi:10.1038/ng.3764.

Miao D, et al. Nat Genet. 2018;doi:10.1038/s41588-018-0200-2.

Reiter JG, et al. Science. 2018;doi:10.1126/science.aat7171.

Russo M, et al. Cancer Discov. 2016;doi:10.1158/2159-8290.CD-15-1283.

Wang Y, et al. Proc Natl Acad Sci USA. 2018;doi:10.1073/pnas.1809232115.

Zhang Y, et al. Nat Cell Biol. 2018;doi:10.1038/s41556-018-0178-0.

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.