Ronald A. DePinho, MD
Glioblastoma multiforme, colorectal cancer, and pancreatic ductal adenocarcinoma represent some of the most difficult-to-treat cancers and collectively cause more than 114,000 deaths each year in the United States. A trio of recently published basic research studies in these cancers have found potential therapeutic targets that may help propel the launch of clinical trials in the treatment of these diseases. Here we summarize the results of the three studies.
In a study of glioma cells in glioblastoma mouse and human glioma stem cell models, the researchers established the key roles of PTEN gene deficiency, YAP1 transcription factor protein activation, and LOX gene expression. Based on these and other mechanisms, they found a symbiotic glioma-macrophage interplay that could provide therapeutic targets for PTEN-deficient glioblastoma.1
With a study based on colorectal cancer mouse models, the researchers investigated whether and how oncogenic KRAS gene mutations might directly influence tumor immunity in colorectal cancer progression and how that knowledge might improve clinical responses to immune checkpoint blockade therapy. The study illuminated predictive response biomarkers as well as potential effective therapeutic strategies to improve clinical responses to immune checkpoint blockade in colo-rectal cancer.2
Finally, in a study using human and mouse model pancreatic ductal adenocarcinoma cell lines, the researches sought to identify and validate USP21 as a pancreatic ductal adenocarcinoma oncogene with the goal of providing a potential druggable target for this common and often lethal cancer—90% of pancreatic cancers are pancreatic ductal carcinomas, and it is the fourth leading cause of cancer-related deaths in the world.3 The study identified USP21 as a therapeutically trackable target for disruption of TCF7-mediated Wnt signaling activation and impairment of pancreatic ductal adenocarcinoma.4
The ASCO Post talked with the principal investigator of these three studies, Ronald A. DePinho, MD, Professor, Department of Cancer Biology, Division of Basic Science Research; Harry Graves Burkhart III Distinguished University Chair in Cancer Biology; and Past President of The University of Texas MD Anderson Cancer Center, about his preclinical study results and how they may drive the design of clinical trials to investigate more effective therapies for glioblastoma, colorectal cancer, and pancreatic ductal adenocarcinoma.
Determining the Drivers of Cancer
Please talk about the importance of the findings from these three studies in the potential treatment of glioblastoma, colorectal cancer, and pancreatic ductal adenocarcinoma.
Much of the work we do in our laboratory is basic research focusing on cancer biology, specifically mechanisms operating in the tumor microenvironment, with an eye toward translational research that will illuminate new clinical opportunities in the treatment of human cancer. To dissect these cancer biologic mechanisms, we use genetically engineered mouse models of human cancer, comparative human and mouse oncogenomics, and integrated mechanistic studies.
In the history of my lab, we have always gone back and forth between studying mouse and human tissue models to understand the complexity of human cancers. We use these models, together with functional and -omic approaches, to understand fundamental disease mechanisms in order to illustrate how genes and pathways connect to tumor biology and vice versa; then, immediately ask whether and how this new knowledge might be relevant to the human situation by performing clinical pathologic correlations in human tumors.
This cross-species approach has been powerful in helping us identify genetic elements that are important drivers of cancer and underlying mechanisms and molecules of cancer that might reveal new therapeutic targets. Over the years, our work has catalyzed the development of over a dozen new drugs that are now in human testing.
We showed that when you combine anti–PD-1 inhibitors with CXCL3 inhibitors, KRAS-mutant colorectal cancer now responds to checkpoint blockade inhibitors.— Ronald A. DePinho, MD
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• Findings in Glioblastoma and Colorectal Cancer: Two of the studies cited here on glioblastoma and colorectal cancer are good examples of how dissecting the complex tumor biology enabled us to identify therapeutic strategies that could lead to additional clinical studies. I hope our results provide ideas for other researchers and biopharmaceutical companies to launch rational human trials with existing drugs or to initiate new drug discovery efforts to find more effective therapies for these difficult-to-treat cancers.
We recently established a colorectal mouse model that faithfully recapitulates the genesis and progression of the human disease, which is driven by oncogenic KRAS mutations and mutational inactivation of TP53 and APC, which are the three most common genetic alterations in human colorectal cancer.
We know that immune checkpoint inhibitors are not effective in KRAS-mutant colorectal cancers. In our study, we found that KRAS negatively regulates IRF2, which in turn represses CXCL3, and that was significant because when KRAS is “turned on,” it results in elevated CXCL3, which recruits myeloid-derived suppressor cells, and these cells inactivate T cells and do not allow immune checkpoint blockades to work. We showed that when you combine anti–PD-1 inhibitors with CXCL3 inhibitors, KRAS-mutant colorectal cancer now responds to checkpoint blockade inhibitors. This result should provide the basis for clinical trials investigating combined CXCR2 and anti–PD-1 inhibition in the treatment of colorectal cancer.
In the glioblastoma study, we asked how specific genetic alterations commonly found in glioma cells may influence the immune composition of the tumor microenvironment, which might inhibit or support the growth of cancer cells, with the goal of identifying therapeutically actionable targets in the tumor microenvironment. We figured out that deletions in the tumor-suppressor gene PTEN activates the YAP1 transcription factor, which regulates expression of LOX, which potently recruits tumor-promoting macrophages into the glioblastoma tumor microenvironment. Taken together, our findings show that PTEN deficiency enhances recruitment of tumor-promoting macrophages, whereas inhibition of LOX reduces these macrophages, restrains tumor growth, and extends survival in human xenograft mouse glioblastoma models. These results should be a motivator in the testing of small-molecule LOX inhibitors (eg, β-aminopropionitrile) in patients specifically with PTEN-deficient glioblastoma.
• Findings in Pancreatic Ductal Adenocarcinoma: As with the glioblastoma and colorectal cancer studies, our interest in investigating the role of USP21 in pancreatic ductal adenocarcinoma was to find potential actionable therapeutic targets that can activate pathways linked to the symbiotic relationship between cancer cells and immune cells. This approach may provide opportunities for attacking the surrogates of those genetic alterations to lead to antitumor responses.
When we surveyed the landscape of genomic changes that occur in pancreatic cancer, we noticed a small but sizable fraction of patients (22%) have amplification of USP21. This caught our attention because USP21 is a druggable target, a rarity in pancreatic cancer.
Our first efforts focused on knocking down USP21 in pancreatic cancer cell lines that overexpressed it to see whether we could impair the malignant properties of those transformed cell lines. These loss-of-function studies, coupled with gain-of-function oncogenic experiments, gave us the confidence that USP21 is a bona fide oncogene in pancreatic cancer and can promote the development of the cancer.
These loss-of-function studies… gave us the confidence that USP21 is a bona fide oncogene in pancreatic cancer and can promote the development of the cancer.— Ronald A. DePinho, MD
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In exploring how USP21 works, we determined that it upregulates the Wnt/beta-catenin pathway, which is known to be upregulated in human pancreatic cancers. That was very exciting because Wnt is considered to be an important pathway for the maintenance of a dedifferentiated state in what is called a cancer stem cell–like phenotype.
Then, we looked at the different components of the Wnt/beta-catenin pathway to see whether any of them are targeted by USP21-directed deubiquitination and, if so, does it impact the activity of that protein target? We found that USP21 was able to deubiquitinate the TCF7 target, which is a downstream transcription factor that carries out the Wnt signaling at the local gene-expression level and regulates many genes involved in pancreatic cancer cell stemness. When USP21 deubiquitinates the TCF7 protein, the TCF7 protein is now more stable and accumulates, resulting in increased expression of TCF7 target genes that are responsible for cancer cell stemness.
Mounting a Drug Discovery Campaign for USP21
Current therapeutic options for pancreatic cancer are largely ineffective. Are there available therapies that could target USP21?
No. There are no drugs currently available that target USP21. However, our work identifies USP21 as a therapeutically trackable target for disruption of TCF7-mediated Wnt signaling activation and impairment of pancreatic ductal adenocarcinoma. So, we are now a step closer to mounting a drug discovery campaign for USP21.
Advancing Treatment Options for Pancreatic Cancer
What are your future plans to study USP21 in the development of pancreatic cancer?
We have more basic science studies underway looking at other aspects of the USP21 dysfunction in the regulation of its cytoplasmic targets in pancreatic cancer cells, because we want to understand more fully the actions of USP21. Should these insights continue to validate it as a therapeutic target, we plan to mount a drug discovery campaign against the USP21 target and hope that others will follow suit as well.
Along these lines, there are several biopharmaceutical companies focused on developing drugs against E3 ubiquitin ligase and the deubiquitinases for cancer and other diseases. We would welcome the opportunity to support their important research for the benefit of patients.■
DISCLOSURE: Dr. DePinho is the founder, director and/or advisor of Tvardi Therapeutics, Asylia Therapeutics, and Nirogy Therapeutics and is a limited partner of Sporos Bioventures.
1. Chen P, Zhao D, Li J, et al: Symbiotic macrophage-glioma cell interactions reveal synthetic lethality in PTEN-null glioma. Cancer Cell 35:868-884, 2019.
2. Liao W, Overman MJ, Boutin AT, et al: KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 35:559-572, 2019.
3. Adamska A, Domenichini A, Falasca M: Pancreatic ductal adenocarcinoma: Current and evolving therapies. Int J Mol Sci 18:E1338, 2017.
4. Hou P, Ma X, Zhang Q, et al: USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation. Genes Dev 33:1361-1366, 2019.