National Fellows Forum Highlights Future Research Directions in HGSOC and HCC

In recent OncLive® National Fellows Forum, oncology fellows gathered to share their research findings, network with other fellows and faculty members, and participate in panels to receive feedback and explore career development strategies.

During the OncLive National Fellows Forum focused on pan tumors, which took place in October 2024 in Miami, Florida, Corinne Jansen, MD, and Nicolae Ciobu Zubenco, PhD candidate, were the cowinners of the event for their presentations, respectively, titled “Ubiquitin C-Terminal Hydrolase L1 Inhibition Drives Cell Metabolism Changes and Exerts Variable Antitumorigenic Effects Dependent on Platinum Status in High-Grade Serous Ovarian Cancer” and “Understanding the Role of Overnutrition on Tumor Metabolism and Antitumor Immunity in MASLD-Related HCC.” Jansen is a gynecologic oncology fellow at Women & Infants Hospital in Providence, Rhode Island, and Zubenco is a PhD candidate in cancer biology at the University of Miami Miller School of Medicine in Florida, and a nondegree PhD student at Columbia University Irving Medical Center in New York, New York.

“It was a great event, and I found it very useful,” Zubenco said in an interview with Oncology Fellows. “The audience was a mix of oncology fellows and some PhD students. Some [individuals] highlighted in-human approaches and others discussed animal models; it was a great mix between these 2 views of more basic and translational research. On the other side, we had a panel of faculty [who] gave us feedback on our research. We went over a few panels about career development, including work-life balance, mentorship, and contract negotiation details.”

UCHL1 Emerges as a Potential Treatment Target in HGSOC

Jansen presented findings from a preclinical study examining the effect of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) on the development of high-grade serous ovarian cancer (HGSOC) and its potential use as a future therapeutic target.1 In the study, Jansen and her coinvestigators examined the efficacy of small molecule inhibition of UCHL1 in HGSOC cell lines via the investigational agent LDN- 57444 and aimed to characterize the proteomic adaptations that resulted from this inhibition in chemotherapy-sensitive and -resistant in vitro HGSOC models.

“UCHL1 is a ubiquitinase protein that has a dual ubiquitin-removing and -adding function, and we believe it is crucial in protein homeostasis. [It also] has been previously identified as having a role in neurodegenerative disease and traumatic brain injury,” Jansen said in an interview with Oncology Fellows. “UCHL1 [has been examined] in different cancer types; in some, it seems to be carcinogenic, [whereas] it seems to be tumor suppressive [in others]. We wanted to look at it in HGSOC because of a previous study showing that it has increased expression with [disease] stage, and it has also been shown to be present in serous tubal intraepithelial carcinoma lesions, which is the precursor lesion to HGSOC. This indicates that it’s probably an early mutation or has increased expression [in HGSOC]. All cancer cells are abnormal, so theoretically, the body should shut it down with apoptosis and programmed cell death. Likely, one of the ways cancer cells avoid this is by figuring out how to overcome the protein homeostasis issue. Ubiquitin is part of that whole process of recycling proteins.”

To conduct their study, Jansen and her coinvestigators compared a dimethyl sulfoxide control cell line with a UCHL1 cell line treated with LDN-57444. They used KEGG analysis to evaluate significant pathway changes and then validated their findings via Western blot analysis. Western blot analysis was also used to compare common cell growth pathway changes that arose following UCHL1 inhibition. Matched chemotherapy-sensitive and -resistant HGSOC cell lines were treated with LDN-57444 in combination with carboplatin, and a cell viability assay was conducted.

Data from proteomic analysis showed that PSAT1, GPT2, MEPCE, and ASNS were all upregulated following small molecule inhibition of UCHL1. Conversely, CEP55, NUMBL, and CD70 were downregulated after UCHL1 inhibition. Findings from the Western blot analysis validated the increases in PSAT1, GPT2, and ASNS, as well as the decreases in NUMBL and CD70.

In the cell viability analysis, UCHL1 inhibition in combination with carboplatin appeared to rescue the chemotherapy-sensitive cell line from the impact of the chemotherapy. In the chemotherapy-resistant cell line, UCHL1 inhibition plus carboplatin displayed a synergistic effect leading to cell death.

“In the chemotherapy-resistant cell line, [UCHL1 inhibition] increased the chemotherapy effect, almost [as if it] restored chemotherapy sensitivity,” Jansen said. “[Additionally], when we examined common cellular growth pathways, we saw that they were upregulated in the chemotherapy-sensitive arm and downregulated in the chemotherapy-resistant arm following UCHL1 inhibition.”

Investigators have developed a UCHL1 knockout mouse model that will be transfected with ovarian cancer cell lines, Jansen added. In the future, the models will be treated with LDN-57444 and chemotherapy to evaluate the effect on tumor burden, Jansen explained.

Overnutrition Promotes Liver Cancer Progression

In his presentation, Zubenco examined how high-fat, high-sugar, Western-style diets could influence the development of hepatocellular carcinoma (HCC), particularly in terms of tumor metabolism and immunity.2 Zubenco and his coinvestigators developed HCC mouse models and fed them either a low-fat standard diet or a high-fat, high-sugar Western diet. Using the hydrodynamic tail vein injection technique, a mix of plasmids was delivered specifically to hepatocytes, inducing the overexpression of MYC and knockout of TP53, leading to cell transformation.

In the introduction, Zubenco noted that metabolic dysfunction–associated steatotic liver disease (MASLD) is the most rapidly growing cause of HCC and is estimated affect approximately 24% of the global population. Chronic consumption of the Western diet leads to obesity, which in combination with a sedentary lifestyle promotes MASLD development. MASLD is a disease that evolves through different stages, from a healthy liver to to steatosis, lobular inflammation, nonalcoholic steatohepatitis, advanced liver fibrosis and cirrhosis, and eventually HCC, Zubenco explained.

Data from the study showed that both female (P = .0026) and male (P = .034) mice that received the Western diet had increased tumorigenesis and lower survival probability over time compared with mice who received the standard diet. The Western diet was also found to promote a dysfunctional state of CD8-positive T-cell–driven antitumor immunity. “We saw that the Western diet induces antitumor immunity dysfunction, meaning the immune system is less capable of attacking the tumor,” Zubenco said.

“We’re trying now to—and this is where the [National Fellows Forum] event was very fruitful—take a translational approach as the next step,” Zubenco
said. “We’re trying to target linoleic acid metabolism [by] inhibiting one of the key limiting enzymes of this metabolic pathway. We have some preliminary data, which indicated that linoleic acid metabolites or intermediates cause immune dysfunction or CD8-[positive] T-cell dysfunction, and we’re trying to develop a potential therapy target, validate it in animal models, and see [whether] this approach can also work in patients.”

References

1. Jansen C, McAdams J, Woodman M, et al. Ubiquitin C-terminal hydrolase L1 inhibition drives cell metabolism changes and exerts variable antitumorigenic effects dependent on platinum status in high-grade serous ovarian cancer. Presented at: OncLive Pan Tumor Fellows Forum; October 18, 2024; Miami, FL.
2. Zubenco NC. Understanding the role of overnutrition on tumor metabolism and antitumor immunity in MASLD-related HCC. Presented at: OncLive Pan Tumor Fellows Forum; October 18, 2024; Miami, FL.