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Newfound Signals Drive Cancer When Protective Gene Fails

A study published in Nature this week reveals new details about the tumor suppressor PTEN, a gene known to be defective in 2 of every 3 people with uterine cancer and in 30 percent of certain breast and brain cancers.

Led by NYU Langone Medical Center and its Perlmutter Cancer Center, the new study found that PTEN normally protects against cancer by preventing a protein called FBXL2 from tagging another protein for destruction. The tagged protein is IP3R3, a “sensor” that recognizes when a cell is multiplying abnormally, and using up more energy than usual, thereby signaling the abnormal cell to self-destruct.

When PTEN is missing, IP3R3 is tagged for degradation by FBXL2, and this important anticancer safety mechanism is disabled.

PTEN has been the subject of study for years because of its better known role of blocking signals in the PI3K/AKT pathway, a driver of growth and survival in most cancer cell types. The new study describes a second way in which defective PTEN helps to promote cancer.

“FXBL2 may be largely responsible for cancer growth in the many patients with genetic changes that happen to disable PTEN,” says senior study author Michele Pagano, PhD, chair of the Department of Biochemistry and Molecular Pharmacology at NYU Langone. “Our results suggest that tumors with altered PTEN should be treated, not only with PI3k/AKT inhibitors currently in clinical trials, but also with drugs that disable FXBL2, to counter both procancer signals driven by defects in this gene.”

“We also showed that an experimental drug—by itself and in combination with a new form of light therapy—countered FBXL2 to let abnormal cells self-destruct,” says Dr. Pagano, also an investigator with the Howard Hughes Medical Institute.

Sensing Cancer

The study results revolve around the role of IP3R3 as a channel that lets calcium pass through membranes between the endoplasmic reticulum (ER), the main calcium source in cells, and mitochondria, “machines” that make cellular energy with the help of calcium. When cells divide and multiply as part of growth, chain reactions activate IP3R3, which, in turn, allows more calcium flow for energy production. The process proceeds unless the channel senses “calcium overload” from growth stimuli that are too strong and triggers cell death.

The Perlmutter Cancer Center researchers found that the protein FBXL2 targets IP3R3 for degradation, and that PTEN competes with FXBL2 as both seek to attach to IP3R3. When PTEN wins, it keeps FXBL2 from attaching an ubiquitin tag that signals to the cell’s “degradation machines” (proteasomes) to break down IP3R3.

When PTEN is missing or defective, FBXL2 tags too much IP3R3 for degradation, and cells can no longer self-destruct, say the authors. To confirm this theory, the research team engineered mice with cancer cells that lacked PTEN. They saw an acceleration of FLBX2-driven breakdown of IP3R3, making these cells less able to self-destruct.

On the other hand, cancer cells engineered to lack the FBXL2 gene became better at self-destructing normally. Interestingly, an analysis confirmed that levels of PTEN and IP3R3 go up or down together in human cancer cells.

Together, the results argue that FBXL2 is a cancer-causing protein in tumors in where PTEN is defective, prompting the researchers to look for ways to block FBXL2 in these cases. To this end, they took advantage of the fact that FBXL2 requires a piece of lipid called geranylgeranyl to home in on the ER membrane near IP3R3. Using a drug called GGTI-2418 (PTX-100), the team blocked the attachment of geranylgeranyl to FBXL2, disabling the enzyme.

PTX-100 was developed by study author Said Sebti, PhD, chair of the Department of Drug Discovery at the Moffitt Cancer Center. Dr. Sebti is also chief scientific officer at Prescient Therapeutics, which has already tested PTX-100 in a phase 1 trial against advanced solid tumors, and is preparing further trials.

Also of note, the research team found that using PTX-100 to block the ability of FBXL2 to target IP3R3 made tumors in mice more vulnerable to photodynamic therapy, or PDT. Based on the ability of photosensitizer drugs to cause toxicity in cancer cells after exposure to light, PDT has been applied in the clinic with encouraging results against several cancers, and is currently in clinical trials for treatment of prostate, brain, and breast cancers.

Experiments showed that PDT significantly reduced tumor weight and cancer growth rate in mice where PTX-100 made sure that IP3R3 was there to trigger cell death. PDT had little effect on cancer cells with depleted supplies PTEN or IP3R3.

Dr. Pagano says his team, in collaboration with Dr. Sebti’s team, is set to study next the effect of combining PTX-100 with PDT in patients with low PTEN, as well as the combination of PTX-100, PDT and P13K/AKT inhibitors.

Along with Dr. Pagano and Dr. Sebti, the study was led by first authors Shafi Kuchay and Carlotta Giorgi in the Department of Biochemistry and Molecular Pharmacology at NYU Langone. Giorgi is also a researcher at the Laboratory for Technologies of Advanced Therapies at the University of Ferrara in Italy. Other study authors from NYU Langone were Daniele Simoneschi and Julia Pagan. Also making important contributions were Sonia Missiroli and Paolo Pinton in Department of Morphology, Surgery and Experimental Medicine at the University of Ferrara; Anita Saraf, Laurence Florens, and Michael Washburn of the Stowers Institute for Medical Research in Kansas City; and Ana Collazo-Lorduy, Mireia Castillo-Martin, and Carlos Cordon-Cardo in the Department of Pathology at the Icahn School of Medicine at Mount Sinai.

This study was funded by National Institutes of Health grants R37-CA076584, R01-GM057587, and R21-CA161108; French Muscular Dystrophy Association/AFM Telethon grant GGP15219/B; Italian Association for Cancer Research grant IG- 18624; Italian Ministry of Education, University, and Research grants COFIN no. 20129JLHSY 002, FIRB no. RBAP11FXBC 002, and Futuro in Ricerca no. RBFR10EGVP 001; and Italian Ministry of Health grant MFAG-13521; as well as by the Italian Cystic Fibrosis Research Foundation, Italian charity Cariplo, and the Stowers Institute for Medical Research.

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