Enzyme that protects against viruses could fuel cancer evolution

An enzyme that defends human cells against viruses can help drive cancer evolution towards greater malignancy by causing myriad mutations in cancer cells, according to a study led by investigators at Weill Cornell Medicine. The finding suggests that the enzyme may be a potential target for future cancer treatments.

In the new study, published Dec. 8 in Cancer Research, scientists used a preclinical model of bladder cancer to investigate the role of the enzyme called APOBEC3G in promoting the disease and found that it significantly increased the number of mutations in tumor cells, boosting the genetic diversity of bladder tumors and hastening mortality.

“Our findings suggest that APOBEC3G is a big contributor to bladder cancer evolution and should be considered as a target for future treatment strategies,”

said study senior author Dr. Bishoy M. Faltas, assistant professor of cell and developmental biology at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.

The APOBEC3 family of enzymes is capable of mutating RNA or DNA—by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an erroneous nucleotide at that position. The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV—they attempt to hobble viral replication by mutating the cytosines in the viral genome.

The inherent hazardousness of these enzymes suggests that mechanisms must be in place to prevent them from harming cellular DNA. However, starting about a decade ago, researchers using new DNA-sequencing techniques began to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the mutations in these tumors were APOBEC3-related—and that these mutations appeared to have a role in helping tumors evade the effects of chemotherapy.

Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations needed for cancerous growth but also boost their ability to diversify and “evolve” thereafter—enabling further growth and spread despite immune defenses, drug treatments, and other adverse factors.

In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all the knockout-only mice survived, whereas nearly a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in the mouse cells was present in the nucleus, where cellular DNA is kept using an ‘optical sectioning’ microscopy technique. Previously, this protein had been thought to reside only outside the nucleus. They also found that the bladder tumors of the APOBEC3G mice had about twice the number of mutations compared to the tumors in knockout-only mice.

Identifying the specific mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had caused a greater mutational burden and genomic diversity in the tumors, likely accounting for the greater malignancy and mortality in the APOBEC3G mice.

“We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from signatures caused by other members of the APOBEC3 family” said Dr. Liu.

Lastly, the researchers looked for APOBEC3G’s mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are linked to worse outcomes.

“These findings will inform future efforts to restrict or steer tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Faltas.

Press release from Weill Cornell Medicine

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Study shows immunotherapy prior to surgery may help destroy high-risk breast cancer

New Haven, Conn. — A new study led by Yale Cancer Center (YCC) researchers shows women with high-risk HER2-negative breast cancer treated before surgery with immunotherapy, plus a PARP inhibitor with chemotherapy, have a higher rate of complete eradication of cancer from the breast and lymph nodes compared to chemotherapy alone. The findings, part of the I-SPY clinical trial, were presented today at the American Association for Cancer Research (AACR) virtual annual meeting.

A new study led by Dr. Lajos Pusztai of Yale Cancer Center shows immunotherapy prior to surgery may help destroy high-risk breast cancer. Credit: Yale Cancer Center

“The results provide further evidence for the clinical value of immunotherapy in early stage breast cancer and suggest new avenues to use these drugs, particularly in estrogen receptor (ER)-positive/HER2-negative breast cancers,” said Lajos Pusztai, M.D., Professor of Medicine (Medical Oncology) and Director of Breast Cancer Translational Research at YCC. Pusztai presented the results of the study today during a plenary session at the AACR meeting.

Physicians treat some women with HER-2 negative breast cancer with chemotherapy before surgery, hoping to shrink the tumor and to guide treatment after the operation. In a subgroup of women, this pre-surgical treatment destroys any evidence of the tumor, achieving what is called “pathologic complete response” (pCR), a condition that typically heralds increased overall survival.

Investigators in the I-SPY 2 clinical trial now report that for women with HER2-negative breast cancer who are treated before surgery, an average pCR rate rises from 22% among those given standard-of-care chemotherapy to 37% in those who received the immunotherapy drug durvalumab, plus the PARP inhibitor drug olaparib, in addition to chemotherapy.

Durvalumab is a checkpoint inhibitor immunotherapy, engineered to unleash immune system T cells against tumors by inhibiting a protein on the surface of T cells called PD-1. PARP inhibitor drugs such as olaparib aim to the ability of impair cancer cells to repair DNA damage caused by chemotherapy.

Overall, 73 patients in the experimental arm were given durvalumab, olaparib, and paclitaxel chemotherapy followed by doxorubicin/cyclophosphamide chemotherapy, while 229 patients in the control arm received the standard treatment of paclitaxel plus doxorubicin/ cyclophosphamide. Researchers analyzed results for all HER2-negative patients, as well as for triple-negative (TNBC) and ER positive subsets. Women with triple negative cancer who received the combination treatment saw a pCR rate of 47%, compared to those given the standard chemotherapy with a pCR rate of 27%. Patients with estrogen-positive/HER2-negative cancer in the experimental arm experienced a pCR rate of 28%, versus 14% for those in the control arm. Patients in the experimental arm, however, were also more likely to experience grade 3 serious adverse events–58% in the experimental arm compared to 41% in the control arm.

Immune-rich cancers showed higher pCR rates in all subtypes and in both treatment arms, but the investigators discovered biomarkers that potentially could identify patients who are most likely to benefit from treatment with durvalumab and olaparib. Among estrogen-positive/HER2-negative cancers, the MammaPrint ultra-high subset benefited the most from the combination, their pCR rate reached 64%. In TNBC, tumors with low CD3/CD8 ratio, high Macrophage/Tcell-MHC class II ratio, and high proliferation appear to have benefited preferentially from adding durvalumab and olaparib to paclitaxel.

I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) 2 is a multicenter phase 2 trial to evaluate novel agents as pre-surgical therapy for breast cancer. The study is a collaboration among 20 U.S. cancer research centers, the U.S. Food and Drug Administration and the Foundation for the National Institutes of Health Cancer Biomarkers Consortium. Lead support for I-SPY 2 came from the Quantum Leap Healthcare Collaborative.

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About Yale Cancer Center and Smilow Cancer Hospital

Yale Cancer Center (YCC) is one of only 51 National Cancer Institute (NCI-designated comprehensive cancer) centers in the nation and the only such center in Connecticut. Cancer treatment for patients is available at Smilow Cancer Hospital through 13 multidisciplinary teams and at 15 Smilow Cancer Hospital Care Centers in Connecticut and Rhode Island. Smilow Cancer Hospital is accredited by the Commission on Cancer, a Quality program of the American College of Surgeons. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment.