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Friday, February 24, 2017

The protein P-S6S240 may serve as an indicator of poor prognosis for patients with a hard-to-treat type of uterine sarcoma called leiomyosarcoma, and preclinical data suggest that patients whose tumors have this protein may respond to PI3K/mTOR inhibitors, according to a study published in Clinical Cancer Research (doi: 10.1158/1078-0432.CCR-16-2149).

"Uterine sarcomas have generally been underexplored due to their rareness; nevertheless, they behave aggressively and are difficult to treat, resulting in a high clinical need," said Frédéric Amant, MD, PhD, a Professor at the Leuven Cancer Institute in Belgium and at the Netherlands Cancer Institute in Amsterdam. "We wanted to generate a clear view on the presence of targetable proteins in all subtypes of uterine sarcomas, with the aim of improving treatment options for these patients."

Amant's team also investigated whether any of the targetable proteins might be potential biomarkers for predicting clinical outcomes. "Identifying biomarkers is crucial because novel treatments are expensive, underscoring the importance of patient selection," he explained.

Amant and colleagues studied five proteins of interest in 288 uterine sarcoma samples, which included 157 leiomyosarcomas, 52 benign uterine stromal tumors, and 41 normal uterine tissues; the rest were endometrial sarcomas, adenosarcomas, and other undifferentiated types of uterine sarcoma.

The researchers found that one of the proteins studied, the activated S6 ribosomal protein P-S6S240, was present more frequently in high-grade tumors (32%) than in low-grade tumors (9%). The presence of this protein was also associated with shorter progression-free survival and disease-specific survival in patients with leiomyosarcoma.

P-S6S240 plays a role in the PI3K/mTOR cell-signaling pathway, a cellular process that stimulates cancer growth, Amant explained.

The team implanted fresh human tumor fragments in mice and generated five leiomyosarcoma patient-derived xenograft (PDX) models. They then treated them with an investigational dual PI3K/mTOR inhibitor and observed tumor shrinkage in two models, a stable tumor in the third model and a decrease in tumor growth in the fourth. The PDX model that did not respond was negative for the activated S6 protein, while all responding models were positive for this protein, suggesting that the activated S6 protein can be a marker for response.

"This, along with our findings that uterine leiomyosarcoma patients with activated S6 protein relapse faster, suggests that P-S6S240 may serve as a prognostic marker," Amant noted.

Earlier versions of mTOR inhibitors that targeted only one of the two active mTOR complexes only achieved mild responses but had substantial toxicity in patients with uterine sarcomas, because of which they did not receive FDA approval for the treatment of sarcoma, Amant explained. "We used a new-generation dual PI3K/mTOR inhibitor [BEZ235; dactolisib] in our preclinical study and were mostly surprised by the efficacy. Such a strong treatment response is rarely seen in leiomyosarcomas," he added. Development of this class of drugs with an acceptable toxicity profile is important.

"Leiomyosarcoma is a neglected field and we now have solid data offering a rationale for testing PI3K/mTOR inhibitors against this disease in clinical trials. Patient participation in such studies is also strongly hoped for," Amant noted.

Uterine sarcomas comprise about 2 to 5 percent of all uterine malignancies, and leiomyosarcomas account for 30 percent of all uterine sarcomas, according to the NCI. Patients with localized disease have a 5-year survival rate of around 50 percent, which declines to 10 to 30 percent for those with metastatic disease, Amant said.

A limitation of the study is that the xenografted mice lack an immune system, therefore, immune-related treatment responses or toxicities cannot be detected using such models.


Tuesday, February 21, 2017

​Cancer mortality rates vary considerably within the growing Hispanic population in the U.S., with significant differences among the major Hispanic ethnic groups, according to a study published in Cancer Epidemiology, Biomarkers & Prevention (doi: 10.1158/1055-9965.EPI-16-0684).

"Hispanic populations are all different, reflecting their country of origin, cultural experiences, and socioeconomic status," said the study's lead author, Paulo S. Pinheiro, MD, PhD, an Associate Professor of Epidemiology at the School of Community Health Sciences at the University of Nevada, Las Vegas. "If we can detect the differences among them, we can more easily identify public health strategies that could decrease their cancer risk and improve health outcomes."

Hispanics accounted for 17 percent of the U.S. population in 2014 and are expected to account for 29 percent of the population by 2060. Cancer is the leading cause of death among Hispanics. In general, cancer incidence and mortality rates are calculated on an aggregate basis, without separating the Hispanic population based on ethnicity or nation of origin. 

In order to compare cancer mortality among various Hispanic ethnic groups, Pinheiro and colleagues analyzed mortality data in Florida residents during the years 2008-2012. The researchers chose to base their study on Florida data because it is the only state with statistically significant representation from all major Hispanic ethnic groups: Cuban, Puerto Rican, Mexican, Central American, Dominican, and South American.

Overall, Pinheiro said, the study showed that Hispanics had a 30 percent lower risk of dying of cancer than non-Hispanic whites. Hispanics had higher mortality rates from stomach and prostate cancer, but lower rates for lung, pancreas, and breast cancer, compared with non-Hispanic whites.

When the researchers examined mortality rates by ethnicity, they found wide variations among groups. Key findings of the study, included:

• Cubans had the highest overall mortality rate for both sexes: 174.1 deaths per 100,000 men and 104.1 deaths per 100,000 women, compared with 158.5 deaths per 100,000 among all Hispanic men and 99.6 per 100,000 for all Hispanic women. By comparison, the mortality rate for non-Hispanic white men was 204.4 deaths per 100,000 and for non-Hispanic white women, the mortality rate was 144.8 deaths per 100,000. Cubans had the highest lung cancer mortality rates of all ethnic groups, which Pinheiro attributed to high smoking prevalence.

• Puerto Ricans had the highest rates of liver cancer among all groups analyzed. Pinheiro said this group may benefit from efforts to increase awareness of risk factors for liver cancer, such as the hepatitis C virus.

• Cubans and Puerto Ricans had higher than average mortality rates from colorectal and endometrial cancers, two types that have been linked to obesity. Pinheiro said this reflects a tendency for immigrants to the U.S. to gain weight as they adopt a typical American diet. Cuban and Puerto Rican women also had higher mortality rates from breast cancer than the other groups. Pinheiro said these women tended to follow the American trend of having fewer children, which has been shown to increase breast cancer risk.

• Prostate cancer mortality among Dominicans was nearly double that of the non-Hispanic whites. Pinheiro said the disparity may reflect the fact that many Dominicans have African ancestry; prostate cancer incidence and mortality is higher in men of African descent.


The study results suggest that as more Hispanics settle in the U.S., they should be cautious about adopting the typical American diet. "They would do well to remember the diets of their home countries," Pinheiro said. "Rice and beans, grains, and fresh fruits and vegetables may be more beneficial than the food they will be exposed to in America."

He added that physicians should counsel their Hispanic patients to follow all recommendations for cancer screening.

"There is undoubtedly better access to screening here than in their home countries, so they should take advantage of it," Pinheiro said. "Depending on where they come from, their doctor could have a more targeted conversation about their cancer risk."

Pinheiro noted that Florida's Hispanic population is mostly foreign-born. He said he expects that the trends shown in this study would apply to Hispanics in most parts of the U.S., but may differ in states like California and Texas, where many Hispanic families have lived for several generations. A limitation of the study is that the amount of time spent in the U.S. was not available for each study participant.

Tuesday, February 14, 2017

Defects in a key gene—long thought to drive cancer by turning off the protection afforded by the BRCA genes—spur cancer growth on their own, according to a study led by researchers from NYU Langone Medical Center (Oncotarget 2017; doi: 10.18632/oncotarget.14637).

The study gene, known as EMSY, has some of the same functions as BRCA1 and BRCA2, which are known to protect against ovarian and breast cancer when normal. When defective, BRCA genes block the body's self-defense against cancer-causing genetic mistakes.

The new data helps explain why some women with healthy BRCA1 and BRCA2 genes develop cancer. The findings may also expand treatment options for the roughly 11 percent of women with ovarian cancer, as well as breast and normal BRCA genes, according to study authors.

"Now that we know exactly how changes in EMSY spur cancer cell growth, we can start to design therapies to specifically target that activity and hopefully stop it," said senior author Douglas Levine, MD, Director of the Division of Gynecologic Oncology at NYU Langone and its Perlmutter Cancer Center.

"This work also suggests that treatments that work for patients with BRCA1 or BRCA2 mutations might also be effective against EMSY-driven cancers because the disease mechanism is similar," added first study author Petar Jelinic, PhD, a Research Assistant Professor at NYU Langone. "The best way to go rapidly from bench to bedside is to find new ways to use existing treatments."

When normal, EMSY, BRCA1, and BRCA2 give the body's cells instructions to create proteins that help repair DNA damage that can cause cancer. When those genes are altered, the repair process fails and cancer grows. Overly active EMSY, like mutated BRCA1 or BRCA2, changes those instructions, so the DNA damage repair process is blocked.

This new study dispels prior theories that EMSY's activation merely turned off the cancer suppression function of BRCA2, noted Jelinic.

Earlier work by Levine and others pointed toward EMSY activation as a culprit in breast and ovarian cancer, but had only examined certain parts of the EMSY protein. The new study was the first to evaluate the full-length EMSY protein and to show that it acts independently of BRCA1 or BRCA2.

Furthermore, the research revealed the part of the EMSY protein is changed by an enzyme called protein kinase A. When there is more active EMSY than normal, this enzyme reacts with the EMSY protein to more thoroughly suppress the DNA repair process.​

Tuesday, February 14, 2017

​A discovery by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore may lead to a new treatment strategy for an aggressive ovarian cancer subtype (Science Signaling 2016;9(448):ra97).

In a study led by Ruby Huang, PhD, principal investigator at CSI Singapore, researchers identified a molecule called AXL that is found to trigger the spread of an aggressive form of ovarian cancer called the Mes subtype. This is one of two aggressive subtypes of ovarian cancer—the other subtype is called Stem-A—that was identified by Huang's group in an earlier study. These two subtypes of ovarian cancers have a higher ability to undergo epithelial-mesenchymal transition.

By carrying out experiments on Mes subtype ovarian cancer cells, researchers found that AXL, when activated, was able to interact with other proteins in the cell to form a cellular pathway that contributes to the aggressive spread of ovarian cancer cells.

Currently, there is no specific treatment for the Mes ovarian cancer subtype, and the findings from this study suggest that blocking AXL could be an effective treatment option for these patients.

"Though earlier studies have suggested the role of AXL in contributing to the spreading of ovarian cancer cells, no study has investigated the AXL function in ovarian cancer with different molecular backgrounds," Huang explained. "This study builds upon our previous efforts in understanding the biology among different ovarian cancer subtypes, and the current finding represents an advancement into novel roles of AXL in ovarian cancer and brings another layer of sophistication in ovarian cancer treatment."

This study was carried out in collaboration with clinicians from the National University Hospital, as well as scientists from Imperial College London, and supported by the National Research Foundation Singapore, Ministry of Education Singapore, and National Medical Research Council.

Tuesday, February 14, 2017

​​The phase II clinical trial of quisinostat, a novel selective oral histone deacetylase inhibitor, met all primary endpoints. The clinical trial is evaluating the efficacy and safety of quisinostat in platinum-resistant ovarian cancer in combination with paclitaxel and carboplatin. The detailed results will be presented in an upcoming clinical research meeting in 2017.

This is a multicenter, open-label study of safety and efficacy of quisinostat in combination with paclitaxel + carboplatin chemotherapy in patients with metastatic or locally advanced epithelial ovarian cancer, primarily peritoneal, or fallopian tube carcinoma, resistant to first-line platinum and paclitaxel-based chemotherapy.

The study consists of a screening period of 3 weeks before the start of quisinostat administration, followed by the treatment period of approximately 18 weeks (up to 6 cycles and 21 days for each cycle), a safety follow-up of 4 weeks after the last administration of the study therapy and post-treatment follow-up aimed at the determination of progression-free survival, time to disease progression, and overall survival rate in the study population.

The main advantage of quisinostat is its unique pharmacokinetic properties, particularly the ability to selectively accumulate in target tissues, providing high potential in treatment of solid tumors, which has been demonstrated in the phase II trial. Quisinostat may present a safe and effective therapeutic solution to patients by restoring sensitivity to chemotherapy in platinum-resistant cases. The efficacy and safety of quisinostat will be further explored in clinic. In 2016, chemistry, manufacturing, and control activities were initiated to support a phase III clinical trial.

The results of a quisinostat phase Ib clinical trial were recently presented at the 2016 European Society for Medical Oncology Congress in Copenhagen, Denmark. Quisinostat demonstrated good safety profile and promising efficacy in metastatic platinum-resistant ovarian cancer, showing the highest objective response rate among other patient groups within the trial.

Preclinical studies have shown quisinostat amplifies HDAC-repressed expression of E-cadherin, leading to a reversal of epithelial-mesenchymal transition. The latter is associated with platinum-based chemotherapy resistance.

Quisinostat has been investigated in six clinical trials in Europe and the U.S. Overall, it has been tested in more than 200 patients with hematological and solid malignancies.

Researchers are planning to study additional indications of quisinostat in combination with proteasome inhibitors to treat translocation-associated sarcomas in adolescents and young adults, and in combination with checkpoint inhibitors to increase efficacy in solid tumors (gynecologic cancers and NSCLC).