Three New Strategies Target Cancer Through Protein Regulation and Immune System Activation

Researchers at VCU Massey Comprehensive Cancer Center found a new angle for fighting lymphoma using a medication already approved for abnormal heart rhythms. In tests, the strategy wiped out cancer cells and slowed tumor growth with little to no toxicity. The work, reported in Pharmacological Research, points to a new direction for precision medicine in cancer by focusing on a part of the target that most drug programs have ignored.

Instead of trying to shut down USP11 by plugging its catalytic machinery, the VCU team aimed at its ubiquitin like (UBL) domain. This region does not carry out the chemical reaction. It acts more like a scaffolding surface that helps USP11 connect with partner proteins. Targeting this domain gave the researchers a way to use structural details that are more unique to USP11, helping separate it from closely related enzymes such as USP4 and USP15.

A structure-based virtual screening effort sifted through more than 10 million compounds to identify candidates predicted to bind the USP11 scaffolding domain. That search ultimately led to RBF4. In follow-up testing, the inhibitors showed strong activity against diffuse large B cell lymphoma cells while largely sparing normal cells, a pattern that supports the goal of selectively disrupting cancer biology without widespread damage.

Diffuse large B-cell lymphoma is the most common and fast-growing type of non-Hodgkin lymphoma, accounting for approximately one in every three lymphomas, according to the American Cancer Society. In relevant preclinical models of MYC-driven lymphoma, RBF4 significantly reduced tumor growth, prevented metastatic spread, and inhibited fluid accumulation, all without observable damage to surrounding tissue.

RBF4 was found to be chemically identical to dronedarone, an FDA-approved medication used to treat irregular heartbeat. This serendipitous discovery opens the possibility of repurposing an existing drug for cancer treatment, potentially accelerating the path to clinical trials by leveraging established safety data.

In separate research, a preclinical study headed by researchers at NYU Langone Health showed how a protein made by stressed cancer cells helps lung and pancreatic tumors evade the immune system. The study found that new drugs designed to block the action of a protein called lipocalin 2 (LCN2) slowed cancer growth in mice by enabling the immune system to target tumor cells. The drugs made aggressive cancers more vulnerable to immunotherapies, which help the immune system attack cancer cells.

The research, published in Nature, centered on a cellular survival pathway called the integrated stress response (ISR), which cells use to endure stressful conditions, such as a lack of nutrients. Cancer cells, with their abnormal, aggressive growth, face a continual threat of starvation, are always stressed, and always have the ISR turned on.

The ISR in cancer cells triggers the production of a protein called activating transcription factor 4 (ATF4), which in turn triggers the action of many genes that help cancer cells survive. The work shows that ATF4 also instructs the cell to release LCN2 to protect the tumor from the immune system.

Studies found that LCN2 passes on the ATF4 message to switch macrophages, a type of immune cell abundant in tumors, into an immunosuppressive mode, which keeps cancer-killing T cells from entering the tumor. When the research team engineered mice to both develop cancer and lack LCN2, tumor growth slowed. That this effect happened only in mice with healthy immune systems suggested that an important role for LCN2 is to block the immune attack on tumors.

Whereas ATF4 operates inside cancer cells, LCN2 is released outside, where it can be more easily targeted by drugs, the researchers said. The team developed an antibody therapy to bind and block LCN2, which kept it from manipulating macrophages, letting the sidelined T cells back into tumors.

When treated with an antibody that blocked LCN2, tumors in mice became flooded with T cells and shrank. Combining the LCN2 antibody with an existing immunotherapy drug worked even better, extending survival in mice with aggressive lung cancer.

The team examined tumor samples from more than 100 lung cancer patients and 30 pancreatic cancer patients. High LCN2 levels were linked to a median survival of 52 months, compared to 79 months for patients with low levels. LCN2 expression in human lung and pancreatic tumors positively correlated with tumor grade, decreased T cell infiltration, shorter overall survival, and poor responses to immunotherapy.