Placental Cells Significantly Inhibit Cancer Cell Growth in Newly Published Study

According to the peer-reviewed article in the journal Scientific Reports, placenta-derived cells called PLX cells, exhibit a strong inhibitory effect on various lines of breast, colorectal, kidney, liver, lung, muscle and skin cancers. The research was conducted over more than two years by Pluristem Therapeutics, Inc., a Haifa-based biotechnology company.

The article titled “Human Placental-Derived Adherent Stromal Cells Co-Induced with TNF‑a and IFN‑g Inhibit Triple-Negative Breast Cancer in Nude Mouse Xenograft Models” is based on studies which examined the effect of Pluristem Therapeutic‘s PLX cells that had been induced with tumor necrosis factor alpha (TNF-a) and interferon-gamma (IFN-g), on the proliferation of over 50 lines of human cancerous cells. The induction of the cells was carried out by adjusting their manufacturing process in order to transiently alter their secretion profile.

Data from the first study showed that the modified PLX cells exhibited an anti-proliferative effect on 45% of the tested cancer cell lines, with a strong inhibitory effect on various lines of breast, colorectal, kidney, liver, lung, muscle and skin cancers. Comprehensive bioinformatics analysis identified common characteristics of the cancer cell lines inhibited by PLX cells. This knowledge could potentially be used in the future for screening patients’ tumors to identify those patients most likely to show a positive response to treatment with PLX cells.

Based on these promising results, Pluristem conducted a pre-clinical study of female mice harboring human triple negative breast cancer (TNBC). TNBC is an aggressive form of breast cancer that does not respond to standard hormonal therapy due to a lack of estrogen and progesterone receptors. Current treatment for TNBC consists of a combination of surgery, radiation therapy, and chemotherapy, and yet the prognosis remains poor for patients with this type of breast cancer. In this study, weekly intramuscular (IM) injections of the induced PLX cells produced a statistically significant reduction (p= 0.025) in mean tumor size in the treated group compared with the untreated group, with 30% of the treated mice exhibiting complete tumor remission. In addition, a statistically significant reduction (p=0.003) was seen in the percentage of proliferating tumor cells as well as in the level of blood vessels within the tumors.

“The findings of this study published in a peer-reviewed journal are the outcome of over two years of research as well as the vast knowledge of PLX cell properties we have developed over the last 10 years. We believe the findings show promise for the utilization of our induced PLX cells in slowing and reversing the growth of cancer cells, particularly for some cancers that don’t have viable treatment options,” stated Zami Aberman, Chairman and Co-CEO of Pluristem. “The findings also confirm the effectiveness of IM administration and support a mechanism of action involving immunomodulation and inhibition of angiogenesis and cell proliferation in cancerous conditions. Our unique patented manufacturing platform allows us to alter our cells’ secretion profile in correlation with the targeted cancer cells, which may open new possibilities in the field of oncology to treat solid tumors and may also offer new paths to help millions of patients around the world. As in immunotherapy technology, PLX cells potentially have the ability to communicate with the body and to secrete biological components that enhance regeneration processes and support the body in fighting cancer cells.”

Pluristem has filed patent applications relating to the technology for the induction of PLX cells and the use of these cells for the treatment of cancer.

Liver Cancer Patients Can Start with Lower Dose of Chemotherapy and Live Just as Long

Penn study shows patients can benefit from fewer side effects and lower treatment costs

Patients with the most common type of liver cancer who are taking the chemotherapy drug sorafenib can begin their treatment with a lower dose than is currently considered standard, and it will not affect how long they live when compared to patients who start on the full dose. That finding comes from a new study from the Abramson Cancer Center of the University of Pennsylvania, published this week in the Journal of Clinical Oncology, and it opens the door for patients with hepatocellular carcinoma to begin with a reduced dose of sorafenib, which helps to minimize the drug’s side effects while also saving money for patients, providers, and insurers.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer among adults and is the second leading cause of cancer-related deaths worldwide. Currently, sorafenib is the only first-line treatment approved for HCC by the U.S. Food and Drug Administration, but its side effects can be particularly difficult on patients. A recent study found 85 percent of HCC patients taking the drug experienced adverse events. In 31 percent of patients on that study, the effects were severe enough to stop treatment. The standard dose sorafenib is 400mg, twice per day.

“Previous studies have started patients with half that dose, escalating only after the patients show they can handle it, but those studies have all been on a smaller scale,” said the study’s lead author Kim A. Reiss, MD, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania. “We wanted to see if we could reproduce those results using a much larger cohort of patients.”

Reiss and her team used a Veterans Health Administration database and identified almost 5,000 HCC patients who were treated with sorafenib between 2006 and 2015, but they couldn’t do a side-by-side analysis of those who received a reduced dose versus those who received the full amount.

“One of the challenges that we faced was that the sickest patients tended to get the reduced dose because of concerns over how much they could tolerate, so any attempt to evaluate these groups based on how long they lived was skewed,” Reiss said.

To solve that problem, researchers looked at patient information to match people from each group based on disease stage, overall health, and other factors. That left them with two groups, each with 1,675 patients.

“Essentially, we used a computer model to simulate putting these patients into a randomized, controlled clinical trial,” said senior author David E. Kaplan, MD, MSc, an assistant professor of Gastroenterology and an associate professor of Medicine at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia.

The controlled data showed the reduced dose had no effect on overall survival. Patients starting at a lower dose had a median survival of 198 days, compared to 195 days for patients starting at the full dose.

In addition, about 40 percent of patients receiving the reduced dose escalated the drug amount within the first two months, while almost 12 percent of standard dose patients had to reduce their level within the same time period.

“It’s important to remember that the reduced dose patients will ramp up as they show they can handle it, while the full dose patients may have to ramp down because of these toxicities, so the dosage levels will converge in the middle,” Reiss said. “All of the patients get the treatment they need, but the reduced dose approach helps keep cost and toxicities down.”

The cost saving was significant. The study found the reduced dose patients took an average of about 100 fewer pills over the course of their treatment. That translated to an average savings of about $3,000 per patient. Reiss noted those numbers are based on VA prices, which tend to be lower than other centers, meaning the real savings for many patients could be even larger.

The researchers note that some doctors are already making use of this practice, which is why they were able to identify so many reduced dose patients for this study, but the majority of physicians are still starting with the full dose.

“Our data suggest starting at a reduced dose is a safe strategy that can be used more commonly,” Reiss said.

This study was supported by research funds from Bayer Healthcare Pharmaceuticals and the VA HIV, Hepatitis, and Related Conditions Programs in the Office of Specialty Care Services.

Liver Cancer Drug Shows Promise in Preventing Liver Fibrosis and Treating NASH

Namodenoson, a Phase II drug developed by Can-Fite BioPharma Ltd. (NYSE MKT: CANF), has shown in newly published data that it prevents liver (hepatic) fibrosis progression in preclinical studies.

“These latest study results add to the growing body of data that demonstrate Namodenoson’s potential efficacy in combating non-alcoholic fatty liver disease (NAFLD), the precursor to non-alcoholic steatohepatitis (NASH), indications for which there is currently no FDA approved drug. We are advancing Namodenoson into a Phase II trial in NAFLD and expect to commence patient enrollment in the coming months through leading medical institutions in Israel,” stated Can-Fite CEO Dr. Pnina Fishman.

NAFLD is characterized by excess fat accumulation in the form of triglycerides (steatosis) in the liver. According to a recent study published in Hepatology, an estimated 25% of the population in the U.S. has NAFLD, with a higher prevalence in people with type II diabetes. Incidence is increasing based on rising obesity rates. NAFLD includes a range of liver diseases, with NASH being the more advanced form, manifesting as hepatic injury and inflammation. According to the NIH, the incidence of NASH in the U.S. is believed to affect 2-5% of the population. The spectrum of NAFLDs resembles alcoholic liver disease; however, they occur in people who drink little or no alcohol. If untreated, NASH can lead to cirrhosis and liver cancer.

By 2025, the addressable pharmaceutical market for NASH is estimated to reach $35-40 billion.

Liver fibrosis is the excessive accumulation of scar tissue resulting from ongoing inflammation. It can result in diminished blood flow throughout the liver and is associated with NAFLD.

Recent preclinical studies in a mouse model of liver fibrosis demonstrated the anti-fibrotic effects of Namodenoson. The Namodenoson treated group exhibited normal liver under macroscopic view, no accumulation of fluid (ascites), a low fibrosis profile, and lower serum levels of transaminases as compared to the control group. In addition, liver protein extracts and mRNA for the alpha smooth muscle actin showed a significant anti-fibrotic effect in the Namodenoson treated group as compared to the control group.

These studies were conducted under the supervision of Prof. Rifaat Safadi M.D., a Key Opinion Leader in the field of liver diseases, and Director of Liver Unit, Institute of Gastroenterology and Liver Diseases, Hadassah University Hospital, Ein Kerem.

Prof. Safadi commented, “Lowering liver fat content and fibrosis are the main unmet needs in NASH. Today there is a huge market need for drugs that fight the worldwide NASH epidemic.”

“Namodenoson is uniquely compelling for its potential to treat NAFLD and NASH because its safety profile has already been de-risked, increasing the likelihood it can advance through late stage trials and into clinical use for this large and unmet need,” Dr. Safadi added. “In general, there is significant development risk for new potential drugs in development due to safety risks including drug induced liver injury (DILI), drug-to-drug interactions (DDI), and metabolites in safety testing (MIST). Namodenoson, however, has demonstrated a good safety profile and is low or negative for DILI, DDI and MIST.”

“In addition, Namodenoson recognizes the difference between diseased and normal cells, and targets only the diseased cells through the specific A3 adenosine receptor. This precision targeting is designed to lead to higher efficacy and safety by leaving healthy cells unaffected. We are all looking for drugs with this profile to treat NASH,” concluded Dr. Safari.

Can-Fite plans to commence patient recruitment for its Phase II trial of Namodenoson in NASH/NAFLD in the second quarter of 2017.

New Biotechnology Partnership Formed to Develop Liver Cancer Chemotherapeutic

Q BioMed, Inc., a New York City-based biomedical acceleration and development company has entered into an agreement with the Oklahoma Medical Research Foundation (OMRF) and the Rajiv Gandhi Centre for Biotechnology (RGCB) to develop a chemotherapeutic technology to treat liver cancer.

The technology will utilize “uttroside B” and the compound’s derivatives as a chemotherapeutic agent against hepatocellular carcinoma. The preclinical efficacy of uttroside B, a potent saponin, against liver cancer was recently demonstrated in a November 3, 2016 study published in Scientific Reports, a Nature journal.

The compound has been isolated and characterized from the leaves of Solanum nigrum Linn, a plant widely used in traditional medicine. In the Scientific Reports study, researchers showed that in animal models, uttroside B was ten times more cytotoxic to the HepG2 liver cancer cell line than the only drug currently approved by the Food and Drug Administration for liver cancer.

Uttroside B drastically shrunk tumors in mice bearing human liver cancer xenografts. In addition, in pre-clinical experiments uttroside B induced cytotoxicity in all liver cancer cell lines, irrespective of their hepatitis B virus status, while being non-toxic to normal immortalized hepatocytes.

Chemotherapeutic options for liver cancer are limited, and the prognosis of patients remains challenging. According to the Centers for Disease Control and Prevention, it is the second most common cause of cancer deaths worldwide, claiming approximately 750,000 lives each year. In the US, the American Cancer Society estimates that 39,000 people will be diagnosed with primary liver cancer in 2017 and that 27,000 will die from the disease this year.

The currently available drug has been shown to increase survival by only a short period of time. That drug also been reported to carry a variety of serious side effects, including increased blood pressure, bleeding problems, decreased blood flow to the heart and heart attacks.

In the Scientific Reports study, uttroside B was shown to be several times more potent than the currently available drug and did not cause noticeable side effects in vitro or in vivo.

“We are encouraged by the preclinical results we observed in this data and look forward to working with our collaborators at OMRF and RGCB to carry out further pre-clinical and clinical evaluation of uttroside B,” Q BioMed Inc. CEO Denis Corin said. “Our ultimate goal is to use it as an effective chemotherapeutic against liver cancer, which currently has very few therapeutic options.”

The uttroside B technology is covered by a provisional patent application. To see the full Scientific Reports study, go to: http://www.nature.com/articles/srep36318

Researchers inhibit tumor growth in new subtype of lung cancer

Lung cancer is the most common cause of cancer deaths, accounting for about a third of all tumor-related deaths. Adenocarcinomas, a non-small cell lung cancer (NSCLC), account for about 40 percent of cancer diagnoses, but few treatments are available for the disease.

A team of investigators led by Elena Levantini, PhD, a research associate in Hematology-Oncology at Beth Israel Deaconess Medical Center (BIDMC), instructor of medicine at Harvard Medical School and a member of the Harvard Stem Cell Institute, have identified a subtype of human adenocarcinoma. The research could help determine which individuals are at greatest risk of developing lung tumors that may be amenable to a new therapy to inhibit their progression. The results – done in collaboration with the Cancer Science Institute at the National University of Singapore (CSI NUS) – were published today in the journal Science Translational Medicine.

“Advances in lung cancer therapy require a greater understanding of the molecular origins of this deadly disease,” said last corresponding author Levantini, who is also a researcher at the Institute of Biomedical Technologies at the Italian National Research Council (ITB-CNR). “Understanding the differences among lung cancers also could lead to innovations in treatment strategies and allow us to overcome drug-resistance, relapse and disease progression.”

Levantini and colleagues previously showed that NSCLC tumor cells frequently express too little or none of a transcription factor called C/EBPα, a protein that regulates gene expression and cell proliferation in lung tissues. It’s also known to play a role in a form of leukemia, as well as liver cancer, squamous cell skin carcinomas, squamous cell cancers of the head and neck and other cancers. In their previous work, the scientists suspected that C/EBPα may act as a tumor suppressant in normal cells, but the mechanism by which its absence promoted lung cancer tumors remained unclear.

In a series of in vitro experiments, the researchers demonstrated that C/EBPα indeed works as a tumor suppressant by restraining the expression of another molecule known to play a role in triggering and maintaining tumor growth. This molecule, called BMI1, is an oncogenic protein that has been implicated in colon cancer, a form of leukemia and breast and gastric cancers.

To determine the relationship between the suspected tumor suppressor (C/EBPα) and the oncogenic protein (BMI1), the researchers first altered a line of human adenocarcinoma cells to overexpress C/EBPα. That led to a marked reduction in the expression of BMI1. When the team analyzed tissues from 261 patients with NSCLC, they found an inverse correlation between the two molecules; that is, more than 80 percent of patient tissues with low levels of the tumor suppressing C/EBPα were positive for BMI1 expression. Likewise, an analysis tissue samples from patients with lung adenocarcinoma with no or low C/EBPα expression revealed that those with lower levels of BMI1 were more likely to survive, a pattern that has prognostic value, the researchers wrote.

“Our findings suggest that the lung cancer subtype defined by the loss of C/EBPα expression might specifically benefit from therapies that inhibit BMI1,” the scientists wrote. “Thus, identifying factors that modulate its expression has generated major clinical interest.”

The research team was also able to validate its findings in mice. In one set of experiments with mice engineered to express no C/EBPα, the scientists found an inverse relationship between the transcription factor and BMI1 that was nearly identical to its data from human adenocarcinoma. By manipulating BMI1 expression in vivo, the researchers were also able to confirm that decreasing the expression of the oncogenic protein was enough to fully inhibit tumor formation and even significantly arrest tumor growth.

“BMI1 plays a substantial role in many solid tumors, including one of the most aggressive models of lung cancer, and its expression is linked with tumor growth, invasion, metastasis, prognosis and recurrence,” Levantini said. “Our findings could help us design better therapies for the subset of adenocarcinoma patients with low C/EBPα and high BMI1 expression pattern.”