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Institute News

Scientists design potential drug for triple-negative breast cancer

AuthorMonica May
Date

February 16, 2021

Noise and artifacts image: MAMMOGRAM Medical image showing CA right breast 3 cm fluid collection at MUQ ,near nipple right breast is noted and this may be seroma

Drug candidate blocks autophagy, a cellular recycling process that cancer cells hijack as a way to resist treatment

Scientists at Sanford Burnham Prebys Medical Discovery Institute have designed a next-generation drug, called SBP-7455, which holds promise as a treatment for triple-negative breast cancer—an aggressive cancer with limited treatment options. The drug blocks a cellular recycling process called autophagy, which cancer cells hijack as a way to resist treatment. The proof-of-concept study was published in the Journal of Medicinal Chemistry.

“Scientists are now learning that autophagy is one of the main ways that cancer cells are able to survive, even in the presence of growth-blocking treatments,” says Huiyu Ren, a graduate student in the laboratory of Nicholas Cosford, PhD, at Sanford Burnham Prebys, and first author of the study. “If all goes well, we hope this compound will stop cancer cells from turning on autophagy and allow people with triple-negative breast cancer to benefit from their treatment for as long as possible.”

Cells normally use autophagy as a way to recycle waste products. However, when cancer cells’ survival is threatened by a growth-blocking treatment, this process is often “revved up” so the cancer cell can continue to receive nutrients and keep growing. Certain cancers are more likely to rely on the autophagy process for survival, including breast, pancreatic, prostate and lung cancers.

“While this study focused on triple-negative breast cancer, an area of great unmet need, we are actively testing this drug’s potential against more cancer types,” says Cosford, professor and deputy director in the National Cancer Institute (NCI)-designated Cancer Center at Sanford Burnham Prebys and senior author of the study. “An autophagy-inhibiting drug that stops treatment resistance from taking hold would be a great addition to an oncologist’s toolbox.”

About 15% to 20% of all breast cancers are triple negative, which means they do not respond to hormonal therapy or targeted treatments. The cancer is currently treated with surgery, chemotherapy and radiation, and is deadlier than other breast cancer types. If the tumor returns, other treatments such as PARP inhibitors or immunotherapy are considered. People under the age of 50 are more likely to have triple-negative breast cancer, as well as women who are Black, Hispanic, and/or have an inherited BRCA mutation.

An optimized drug

In this study, the scientists optimized a first-generation drug they created in 2015. The result is a compound called SBP-7455 that blocks two autophagy proteins, ULK1 and ULK2. SBP-7455 exhibits promising bioavailability in mice and reduces autophagy levels in triple-negative breast cancer cells, resulting in cell death. Importantly, combining the drug with PARP inhibitors, which are currently used to treat people with recurrent triple-negative breast cancer, makes the drug even more effective.

“We are hopeful that we have found a new potential therapy for people living with triple-negative breast cancer,” says Reuben Shaw, PhD, a study author and professor in the Molecular and Cell Biology Laboratory and director of the NCI-designated Cancer Center at the Salk Institute. “We envision this drug being used in combination with targeted therapies, such as PARP inhibitors, to prevent cancer cells from becoming treatment resistant.”

Next, the scientists plan to test the drug in mouse models of triple-negative breast cancer to confirm that the compound can stop tumor growth in an animal model. In parallel, they will continue optimization efforts to ensure the drug has the greatest chance of clinical success.

“Triple-negative breast cancer is one of the hardest cancers to treat today,” says Ren. “I hope that our research marks the start of a path to successful treatment that helps more people survive this aggressive cancer.”

Additional study authors

Additional study authors include Nicole A. Bakas, Mitchell Vamos, Allison S. Limpert, Carina D. Wimer, Lester J. Lambert, Lutz Tautz, Maria Celeridad and Douglas J. Sheffler of Sanford Burnham Prebys; Apirat Chaikuad and Stefan Knapp of the Buchmann Institute for Molecular Life Sciences and Goethe-University Frankfurt; and Sonja N. Brun of the Salk Institute.

Research funding 

This work was supported by the National Institutes of Health (P30CA030199, T32CA211036), Epstein Family Foundation, Larry L. Hillblom Foundation (2019-A-005-NET), Pancreatic Cancer Action Network (19-65-COSF), SGC—a registered charity that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking (875510), Janssen, Merck KGaA, Merck & Co, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome.

The study’s DOI is 0.1021/acs.jmedchem.0c00873.

Institute News

Mining “junk DNA” reveals a new way to kill cancer cells

AuthorMonica May
Date

February 11, 2021

DNA strand and Cancer Cell Oncology Research Concept 3D rendering, abstract background

Scientists unearth a previously unknown vulnerability for cancer and a promising drug candidate that leverages the approach

Scientists at Sanford Burnham Prebys have uncovered a drug candidate, called F5446, that exposes ancient viruses buried in “junk DNA” to selectively kill cancer cells. Published in the journal Cell, the proof-of-concept study reveals a previously unknown Achilles’ heel for cancer that could lead to treatments for deadly breast, brain, colon and lung cancers.

“We found within ‘junk DNA’ a mechanism to stimulate an immune response to cancer cells, while also causing tumor-specific DNA damage and cell death,” says Charles Spruck, PhD, assistant professor in the National Cancer Institute (NCI)-designated Cancer Center and senior author of the study. “This is a very new field of research, with only a handful of papers published, but this has the potential to be a game-changer in terms of how we treat cancer.”

Since the human genome was fully sequenced in 2003, scientists have learned that our DNA is filled with some very strange stuff—including mysterious, noncoding regions dubbed “junk DNA.” These regions are silenced for a reason—they contain the genomes of ancient viruses and other destabilizing elements. An emerging area of cancer research called “viral mimicry” aims to activate these noncoding regions and expose the ancient viruses to make it appear that a cancer cell is infected. The hypothesis is that the immune system will then be triggered to destroy the tumor.

A one-two punch to cancer

In the study, Spruck and his team set out to find the molecular machinery that silences “junk DNA” in cancer cells. Using sophisticated molecular biology techniques, they found that a protein called FBXO44 is key to this process. Blocking this protein caused the noncoding sections of DNA to unwind—but not for long.

“When we revealed noncoding regions, which aren’t meant to be expressed, this caused DNA breakage. This told the cell that something is deeply wrong, and it committed suicide,” explains Spruck. “At the same time, the DNA of the ancient virus was exposed, so the immune system was recruited to the area and caused more cell death. So, we really delivered a one-two punch to cancer.”

The scientists then showed that a drug that targets the FBXO44 pathway, called F5446, shrank tumors in mice with breast cancer. The drug also improved the survival of mice with breast cancer that were resistant to anti-PD-1 treatment, an immunotherapy that is highly effective but often stops working over time. Additional studies in cells grown in a lab dish showed that the drug stops the growth of other tumors, including brain, colon and lung cancers.

The scientists also conducted many experiments to show that this silencing mechanism only occurs in cancer cells, not regular cells. Analysis of patient tumor databases confirmed that FBXO44 is overproduced in many cancers and correlated with worse outcomes—further indicating that a drug that inhibits this protein would be beneficial.

Moving the research toward people

As a next step, the scientists are working with the Conrad Prebys Center for Chemical Genomics to design an FBXO44 pathway-inhibiting drug that is more potent and selective than F5446. This state-of-the-art drug discovery facility is located at Sanford Burnham Prebys.

“Now that we have a compound that works, medicinal chemists can make modifications to the drug so we have a greater chance of success when we test it in people,” says Jia Zack Shen, PhD, staff scientist at Sanford Burnham Prebys and co-first author of the study. “Our greatest hope is that this approach will be a safe and effective pan-cancer drug, which maybe one day could even replace toxic chemotherapy.”