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Division of Cancer Therapeutics
Introduction of Laboratory
In the field of cancer therapeutics, we are engaged in research aimed at "curing cancer with drugs."We focus on genetic abnormalities, which are the most characteristic of cancer, and aim to develop personalized cancer therapies based on genetic abnormalities characteristic of each cancer patient. In order to apply cancer treatment methods clinically, it is important to clarify the reasons why they are effective. By selecting cancer drugs based on scientific evidence, rather than blindly using anticancer drugs, we can expect cancer treatment with a low burden that is suitable for each patient. Therefore, in our laboratory, we aim to develop a cancer treatment method by following three steps.
- Discover promising therapeutic target molecules for cancers with certain genetic abnormalities.
- We will elucidate the molecular mechanism of how cancer is suppressed.
- We will collaborate with pharmaceutical companies to develop drugs and aim for clinical applications.
Press Releases
Here are some press releases from our laboratory and our researchers.- June 26, 2024 SMARCB1 Discovery of Promising Therapeutic Targets and Inhibitors for Gene-Deficient Pediatric and AYA Cancers
- January 25, 2019 Discovery of a new cancer treatment targeting metabolism (metabolome) for ARID1A gene-mutated cancers found in ovarian clear cell carcinoma, which is common in Japan
- December 9, 2015 Discovery of a new cancer therapeutic target based on synthetic lethality
Main Papers
Sasaki M, Kato D, Murakami K, Yoshida H, Takase S, Otsubo T, Ogiwara H.
Targeting dependency on a paralog pair of CBP/p300 against de-repression of KREMEN2 in SMARCB1-deficient cancers.
Nat Commun. 2024 15(1):4770.
https://pubmed.ncbi.nlm.nih.gov/38839769/
Ogiwara H., Takahashi K., Sasaki M., Kuroda T., Yoshida H., Watanabe R., Maruyama A., Makinoshima H., Chiwaki F., Sasaki H., Kato T., Okamoto A., Kohno T.
Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers.
Cancer Cell. 35:177-190.e8. 2019
https://pubmed.ncbi.nlm.nih.gov/30686770/
Ogiwara H., Sasaki M., Mitachi T., Oike T., Higuchi S., Tominaga Y., Kohno T.
Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality via apoptotic cell death due to abrogation of MYC expression
Cancer Discov. 6(4):430-445. 2016
https://pubmed.ncbi.nlm.nih.gov/26603525/
Oike T., Ogiwara H., Tominaga Y., Ito K., Ando O., Tsuta K., Mizukami T., Shimada Y., Isomura H., Komachi M., Kohno T.
A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.
Cancer Res. 73:5508-5518. 2013
https://pubmed.ncbi.nlm.nih.gov/23872584/
Synthetic Lethal Therapy Based on Targeting the Vulnerability of SWI/SNF Chromatin Remodeling Complex-Deficient Cancers.
Cancer Science. 111(3):774-782. 2020
https://pubmed.ncbi.nlm.nih.gov/31955490/
Main Research Topics
Development of new cancer therapies using synthetic lethality
Cancer genomic medicine is a personalized cancer treatment based on genetic abnormalities in cancer. Conventional cancer genomic medicine is a treatment for cancers with activated genetic abnormalities, such as oncogenes. In cancers with activated genetic abnormalities, it can be expected that cancer can be suppressed by inhibiting the activated proteins generated by the abnormalities with drugs. So far, many "oncogenes" that cause activated genetic abnormalities have been discovered, and drugs that suppress these genetic abnormalities have been put to practical use in clinical practice. However, such activated genetic abnormalities are limited to some cancers. Other cancer-causing genetic abnormalities are genetic abnormalities that are deficient (loss-of-function) of tumor suppressor genes. When a defective genetic abnormality occurs in a tumor suppressor gene, the protein made based on the gene has lost its function and cannot be inhibited by drugs. However, when a defective genetic abnormality occurs, cancer cells rely on a gene other than the genetic abnormality to maintain the growth of cancer cells. Therefore, it can be expected to suppress cancer by inhibiting the factors that cancer cells with defective gene abnormalities rely on for survival (synthetic lethal factor) with drugs. Although many deficient genetic abnormalities have been found so far, the search for synthetic lethal factors for these genetic abnormalities has only just begun. In the future, it is expected that the development of therapies using inhibitors of synthetic lethal factors (synthetic lethal therapy) for cancers with defective genetic abnormalities will be developed. In particular, in refractory cancers, it has been found that there are only a few abnormalities in oncogenes, and most of them are defective genetic abnormalities. In other words, the development of therapies for defective genetic abnormalities will lead to the development of treatments for refractory cancers.Conventional Cancer Genomic Medicine
Recent rapid development of genome sequencing technology has made it possible to decode the genome of each cancer patient's cancer cell Mr./Ms.. Since June 2019, cancer gene panel testing has been covered by insurance in Japan, and "cancer genomic medicine" has begun to provide optimal cancer treatment based on genetic abnormalities in cancer. In the future, by understanding the genetic abnormalities of individual cancer cells, it will be possible to promote personalized medicine for each cancer patient Mr./Ms.. For example, genetic abnormalities such as EGFR gene mutations, ALK gene fusions, and RET gene fusions found in lung cancer lead to the activation of kinase proteins, which are key to the growth of cancer cells. In other words, such cancer cells depend on activated oncogenes to survive. Therefore, by using inhibitors of activated oncogene products (proteins), it is possible to specifically suppress the proliferation of cancer cells with abnormalities in oncogenes. In fact, when the genomic DNA of lung cancer cells of Mr./Ms. lung cancer patients is detected, EGFR gene mutations, ALK gene fusions, and RET gene fusions are detected, and treatment with inhibitors of these drugs has already been implemented in clinical practice. In this way, molecularly targeted therapies targeting activated gene abnormalities occurring in cancer cells are more selective for cancer than conventional anticancer drug treatments, and are expected to be highly effective treatments (optimized cancer treatments, precision medicine, precision medicine).Development of new cancer genomic medicine based on the theory of "synthetic lethality"
Genetic abnormalities found in cancer not only cause activation, but also cause loss of activity. Abnormalities in the BRCA1 and BRCA2 genes seen in hereditary breast cancer and ovarian cancer are thought to contribute to cancerization by the loss of function of the genes due to genetic abnormalities that cause a lack of function. Tumor suppressor genes with such defective abnormalities have lost their function in the first place, so treatment that inhibits the function of the gene itself with drugs is not possible. However, human cells are equipped with a backup function for various genes for cell proliferation. If we can inhibit the function of the gene that backs up such cancers, we can kill cancer cells (the relationship between BRG1 and BRM; Oike, Ogiwara et al., Cancer Res, 2013) (relationship between CBP and p300; Ogiwara et al., Cancer Discov, 2016）。 Or, if a gene loses its function due to mutations in cancer cells, the gene may stop functioning, and although the cell will not die by itself, the function associated with the gene may be weakened. In other words, it creates a "weakness" in cancer cells. And if you inhibit the gene (protein) that supports this vulnerability, you can exploit the weakness of cancer cells and kill them (relationship between ARID1A and GCLC; Ogiwara et al., Cancer Cell, 2019）。 In this way, when a defective gene abnormality occurs, cancer cells are sometimes considered to rely on other genes to survive (dependence) or to survive with weaknesses (vulnerability).In cancer that has lost the function of a certain gene A, if gene B is inhibited due to a lack of gene A function and is dependent or weak, cancer cells will die, which is called "synthetic lethality". In other words, the loss of both gene A and gene B functions and the phenomenon in which cells become lethal is "synthetic lethality". In breast cancer and ovarian cancer with defective genetic abnormalities such as BRCA1 and BRCA2 genes, PARP1 is a synthetic lethal factor, and administration of PARP1 inhibitors has shown a therapeutic effect by synthetic lethality in BRCA1 or BRCA2-deficient cancers, and is currently being applied clinically.
In this way, molecularly targeted therapy targeting synthetic lethal factors based on cancer-deficient genetic abnormalities has little effect on normal cells and can be expected to specifically suppress cancer cells. Cancer treatment methods using "synthetic lethality" (synthetic lethal treatments) are expected to be a new approach to cancer treatment.
Development of synthetic lethal therapies for chromatin regulating gene-deficient cancers
Conventional molecularly targeted therapies are applied to cancer patients with genetic abnormalities that activate oncogenes. However, in reality, this Mr./Ms. of cancer patients is only applicable to some Mr./Ms. cancer patients. In order to make effective drug therapy available to more cancer patients, it is necessary to develop synthetic lethal therapies for cancer patients with defective genetic abnormalities such as tumor suppressor genes Mr./Ms. that are not oncogenetic. Recent genomic analyses by next-generation sequencers have revealed that many chromatin regulatory genes are mutated at a high frequency in various cancers. In other words, the chromatin regulatory genes in which these defective genetic abnormalities occur are considered to be tumor suppressor genes.Chromatin regulators are factors involved in the control of chromatin structure. Chromatin regulators can be broadly classified into chromatin remodeling complexes and histone modifiers. The chromatin remodeling complex controls the state of chromatin aggregation by moving or removing nucleosomes wrapped around the chromatin to maintain the homeostasis of the chromatin structure. Histone modifiers also regulate histone-DNA interactions by methylating, acetylating, and ubiquitinating the histones that make up nucleosomes, and control chromatin remodeling complexes, transcription factors, and other binding to chromatin. Thus, chromatin regulators are not only involved in transcription-mediated development and differentiation by transforming chromatin structures, but also in chromosomal stability via DNA repair, DNA replication, and chromosomal segregation.
Defects in chromatin regulatory genes in cancer cells are thought to create some kind of vulnerability or dependence. And since it is a weakness for cancer, it is thought that cancer can be suppressed by inhibiting that weakness with drugs. In this way, based on genetic abnormalities, which are the difference between normal cells and cancer cells, we can find weaknesses in cancer, which leads to the establishment of promising cancer treatments.
Development from conventional synthetic lethality to next-generation synthetic lethality
Currently, information on genetic abnormalities and dependent genes (genes that are lethal if suppressed in each cell) in more than 1,000 types of cancer cells is stored in a database on the DepMap site. By utilizing this database, it is possible to conduct a genome-wide search for synthetic lethal genes for genetic abnormalities in cancer. However, this relationship between synthetic lethality is a "one-to-one" correspondence of synthetic lethality that targets one synthetic lethal gene (protein) for one genetic abnormality in cancer. Currently, the conventional "one-to-one" response to synthetic lethal therapy is applied to the treatment of cancer. Originally, synthetic lethality was a phenomenon in which a cell becomes lethal when two genes in the cell are suppressed at the same time. In other words, conventional synthetic lethality is synthetic lethality between two genes. Next-generation synthetic lethality can also be considered synthetic lethality between three or more genes. As a next-generation synthetic lethal treatment that is expected in the future, it is a method of inducing synthetic lethality between three genes by simultaneously inhibiting two genes (proteins) for a single genetic abnormality in cancer. However, in order to search for synthetic lethal genes based on the next-generation "1-to-2" synthetic lethality in a genome-wide manner, the problem is how to combine two proteins that inhibit at the same time. When considering the combinations of all human genes in a genome-wide manner, the total number of combinations of each pair is more than 10,000 times that of the "one-to-one" correspondence among the approximately 20,000 genes targeted by general comprehensive target search methods. "One-to-one" genome-wide target search methods have already reached their technical limits. At present, it is not feasible to establish a genome-wide target search method that is more than 10,000 times larger than 10,000 times that of a genome-wide target. Therefore, we thought that in the search for synthetic lethal targets based on the next-generation "1-to-2" correspondence synthetic lethality, we would like to paralog two targets that inhibit at the same time. Paralogs are similar proteins with high homology. Since the two proteins that are paralogs (paralog pairs) have similar protein structures, it is possible to inhibit two proteins of the paralogs at the same time with a single inhibitor. Based on this concept, we devised the "paralog simultaneous inhibition method" as a search method for synthetic lethal targets with a next-generation "1-to-2" correspondence. An important advantage of the "simultaneous paralog inhibition method" is the ability to identify synthetic lethal targets by simultaneous two-factor inhibition, such as paralog pairs, which could not be detected by conventional "one-to-one" correspondence synthetic lethality-based target search methods. So far, we have been conducting research to search for synthetic lethal paralog pairs in SMARCB1-deficient cancers, which are SWI/SNF chromatin remodeling complex factors, using the "simultaneous paralog inhibition method". As a result, we identified a paralog pair of CBP/p300, a histone acetylase. In SMARCB1 normal cell line group, cells can survive even if CBP and p300 are suppressed at the same time, but in SMARCB1-deficient cell lines, simultaneous suppression of CBP/p300 will cause the cells to die. In this case, inhibition of CBP or p300 alone in SMARCB1-deficient cell lines shows only partial growth suppression. This phenomenon is exactly the kind of one-to-two synthetic lethality. In other words, for a single genetic abnormality in cancer (SMARCB1-deficient aberration), synthetic lethality was induced when two targets (CBP and p300) of the paralog pair were inhibited at the same time. Therefore, we have discovered a next-generation "one-to-two" synthetic lethality that exhibits synthetic lethality by simultaneously inhibiting the paralog pair (two factors) of CBP and p300 in SMARCB1-deficient cancers (Sasaki et al., Nature Communications, 2024)（2024年6月26日プレスリリース）. Currently, we have established a genome-wide drug discovery target search method based on the "paralog simultaneous inhibition method" in order to search for synthetic lethal targets based on the next-generation "1-to-2" correspondence synthetic lethality in a genome-wide manner. In the future, we Thailand to establish cancer therapies that can contribute to unmet medical needs for refractory cancers such as lung cancer, diffuse gastric cancer, pancreatic cancer, esophageal cancer, and ovarian clear cell carcinoma, as well as pediatric cancers such as rhabdoid tumors, epithedioid sarcoma, and synovial carcinoma (juvenile cancers) using next-generation synthetic lethal target searches.We aim to develop individualized cancer therapies based on scientific evidence by identifying synthetic lethal factors based on defective genetic abnormalities in cancer and elucidating the mechanism of action. To this end, it is also important to develop inhibitors that target synthetic lethal factors. To this end, we are also conducting drug discovery and development in collaboration with pharmaceutical companies. As an ultimate goal, we aim to develop promising cancer drugs based on synthetic lethality and "cure cancer with drugs."
