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.

Combo immunotherapy may herald new standard of care for kidney cancer

Combination therapy with two immunotherapy drugs produces an unprecedented doubling of response rates from 20 percent to 40 percent, a new study shows.

The multicenter trial involving 100 patients showed that the addition of ipilimumab to nivolumab, which is currently FDA-approved for treatment of kidney cancer, leads to responses that can last beyond two years. Half of the patients in the study, which appears in the Journal of Clinical Oncology, had metastases that had grown while they were on previous therapy.

“For this group of patients, these are very significant results,” said lead author Dr. Hans Hammers, Associate Professor of Internal Medicine and co-leader of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center.

The results set the stage for a pivotal Phase III trial, which has completed enrollment of patients. Should the results of this study be repeated in the larger Phase III trial, it would lead to a new standard of care for kidney cancer patients, said Dr. Hammers, formerly of Johns Hopkins medical system, who holds the Eugene P. Frenkel, M.D. Scholar in Clinical Medicine at UT Southwestern.

While significant advances in the treatment for kidney cancer over the last decade have led to the approval of a dozen drugs, these drugs are mostly palliative, lacking the potential for cure. “By contrast, durable responses lasting many years can be achieved with immunotherapy,” said Dr. Hammers.

Activation of the immune system, however, can lead to serious complications, requiring potent anti-inflammatory drugs. “While side effects of immunotherapy can be significant, they are typically reversible, and unlike current therapies, don’t significantly dampen patients’ daily quality of life,” said Dr. Hammers.

“Given the potential severity of the adverse effects, patients benefit from expert management available at centers of excellence,” said Dr. James Brugarolas, Associate Professor of Internal Medicine and Leader of the Kidney Cancer Program at UT Southwestern.

Ongoing efforts in the Kidney Cancer Program focus on leveraging Nobel Prize-winning discoveries from UT Southwestern’s Dr. Bruce Beutler leading to a new family of proteins that activate the immune system, the toll-like receptors. “Another avenue we are exploring, is the combination of immunotherapy and radiation,” said Dr. Brugarolas.

Nobel Laureate Dr. Beutler, Regental Professor and Director of the Center for the Genetics of Host Disease, discovered an important family of receptors that allow mammals to sense infections when they occur, triggering a powerful inflammatory response. For this work, he received the 2011 Nobel Prize in Physiology or Medicine. Dr. Beutler, also Professor of Immunology, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

Kidney cancer is the sixth most common cancer type affecting both men and women. Classic chemotherapy has never worked well for kidney cancer. Targeted therapies have prolonged life expectancy, but are associated with daily side effects. Single-agent immunotherapies improve patients’ survival, but only benefit a subset of patients. Combination immunotherapy with nivolumab and ipilimumab as tested in the kidney cancer study described here is already FDA-approved for treatment of melanoma, and is being tested for other cancers.

The Kidney Cancer Program at UTSW is one of two programs in the U.S. recognized with a Specialized Program of Research Excellence award by the National Cancer Institute. Discoveries at the Kidney Cancer Program have led to a new understanding of how kidney cancer develops and are leading to new treatments.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 48 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Comprehensive Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Comprehensive Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

New HIF-2 Kidney Cancer Therapy More Effective Than Current Treatment, Study Shows

A new class of drugs called HIF-2 inhibitors is more effective and better tolerated than the standard of care drug sunitinib in treating kidney cancer, researchers with the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center have found.

HIF-2 inhibitors, which grew out of research begun more than 20 years ago at UT Southwestern Medical Center, work by interfering with processes that fuel the growth of cells.

Investigators conducted a pre-clinical trial in mice transplanted with kidney cancer from over 20 patients and showed that the HIF-2 inhibitor PT2399 controlled cancer in half of the tumors, according to a study published in the journal Nature.

“This is a completely new treatment for kidney cancer. We want to make HIF-2 inhibitors available to patients and are currently carrying out clinical trials,” said Dr. James Brugarolas, Director of the Kidney Cancer Program, who is leading an $11 million SPORE grant from the National Cancer Institute seeking to translate new discoveries into novel therapies for kidney cancer patients. Part of the SPORE grant, one of just two directly related to kidney cancer in the nation, is focused on further researching HIF-2 inhibitors.

In a previous report, Dr. Kevin Courtney, Assistant Professor of Internal Medicine and a coauthor of the current study, reported at the American Association of Clinical Oncologyannual meeting that HIF-2 inhibitors were safe in patients and had activity even in heavily pretreated patients. In the study in Nature, investigators show that HIF-2 inhibition was able to control metastatic kidney cancer even after 7 lines of prior therapy. See video.

The findings show that HIF-2 is a promising target to combat kidney cancer, said Dr. Brugarolas, senior author and a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern.

Nearly 400,000 Americans are now living with a diagnosis of kidney cancer and more than 60,000 people are expected to be diagnosed with kidney cancer this year, according to the National Cancer Institute. Texas has the fifth highest rate of this cancer in the U.S.

What is HIF-2

HIFs or hypoxia-inducible factors, like HIF-2, allow the body’s cells to adjust to low-oxygen environments. HIFs activate programs that promote the development of blood vessels, facilitate oxygen delivery and promote efficient nutrient utilization. Kidney cancer cells hijack the same system to fuel their growth.

HIF-2 inhibitors work by suppressing the effects of HIF-2 which include downregulating an important protein called VEGF that promotes the formation of blood vessels needed for tumors to grow.

“Unlike existing VEGF inhibitors, the HIF-2 inhibitor blocks VEGF only in the cancer and thereforedoes not cause cardiac toxicity or hypertension,” Dr. Brugarolas explained.

New HIF-2 findings

In the Nature study, researchers compared the two drugs head to head and found that the HIF-2 inhibitor was more active than sunitinib and that it was active against tumors progressing on sunitinib.

“Furthermore, it was also better tolerated. As sometimes happens in patients, mice on sunitinib were sickly and lost weight, whereas mice on the HIF-2 inhibitor gained weight while on the study,” he said.

Researchers surprisingly found a subset of tumors that do not respond to the drug, but were able to identify biomarkers that, once verified, would help determine which patients are more likely to benefit from HIF-2 therapies.

“HIF-2 is believed to be the most important driver of kidney cancer. Traditionally, proteins like HIF-2 were disregarded as drug targets because their shape made it nearly impossible to design drugs against them,” Dr. Brugarolas said. “The approaches we have taken pave the way for identifying drug candidates for other proteins that have traditionally been considered undruggable.”

HIF-2 also appears significant in other types of cancer, including deadly brain cancers called glioblastomas and non-small cell lung cancer, the most common type of lung malignancy.

How HIF-2 came to be

In 1997, UT Southwestern researchers Dr. Steven McKnight, Chairman of Biochemistry, and molecular geneticist Dr. David Russell, Vice Provost and Dean of Basic Research, led research discovering and describing the protein encoded by the EPAS1 gene, also known as HIF-2α, the main HIF-2 component. Over the course of a decade, the laboratories of Dr. Richard Bruick, Professor of Biochemistry, holder of the Michael L. Rosenberg Scholar in Biomedical Research, and a coauthor of the current study, and Dr. Kevin Gardner, Adjunct Professor of Biochemistry, solved the structure of HIF-2α.

By 2009, researchers had identified a “sweet spot” where drugs could bind and shut down HIF-2 activity. Using the Simmons Cancer Center’s High-Throughput Screening, scientists tested more than 200,000 chemicals to see which ones could interfere with HIF-2, identifying several potential drug-like compounds. The most promising compounds were licensed to Peloton Therapeutics, Inc., a biotech firm co-founded by Dr. McKnight and based at UT Southwestern’s BioCenter campus. In 2014, the first HIF-2 inhibitor, an oral drug known as PT2385, entered clinical trials in patients with advanced or metastatic renal clear cell carcinoma.

HIF-2 inhibitors also are the target of UTSW’s recent $11 million SPORE (Specialized Program of Research Excellence) award. Investigators will further biomarkers to identify patients most likely to respond to the HIF-2 inhibitor, as well as to anticipate ways in which the tumor may evade the drug’s impact.

UT Southwestern’s SPORE program involves four innovative disease and clinical research teams targeting adult and pediatric kidney cancer. Other UTSW SPORE investigators are looking at the function of a gene that identifies a cluster of particularly aggressive tumors, in hopes of identifying vulnerabilities that can be targeted with drugs; examining kidney cancer metabolism to distinguish aggressive from less active tumors, potentially yielding a tailored treatment approach; and evaluating novel subtypes of childhood kidney cancer.

Study Suggests Link Between Obesity and Kidney Cancer

Receptors for leptin, a protein hormone, may be associated with tumor recurrence in patients with renal cell carcinoma (RCC), providing further understanding about molecular links between obesity and RCC tumor formation and prognosis, according to a study at The University of Texas MD Anderson Cancer Center.

The findings are being presented April 18 at the annual meeting of the American Association of Cancer Research (AACR) in New Orleans.

The leptin receptors, called LEPR, were found to be hypermethylated in tumors in a study involving 240 newly diagnosed and previously untreated Caucasian RCC patients. Methylation is a mechanism by which cells control gene expression and both hypomethylation and hypermethylation are known to play roles in silencing of tumor suppressor genes or over-expression of oncogenes in cancer cells. LEPR was one of 20 obesity-related genes that the research team examined.

“Obesity is an established risk factor for RCC with more than 40 percent of these cases attributed to excessive body weight,” said Xifeng Wu, M.D., Ph.D., professor of Epidemiology and principal investigator for the study. “Growing evidence suggests that obesity also may be associated with the prognosis of RCC. The molecular mechanism LEPR and two other genes, NPY and LEP, are involved in RCC tumorigenesis. LEPR methylation in tumors is associated with recurrence in RCC patients and thus, LEPR may provide a functional link between obesity and RCC.”

The study evaluated the association between methylation of 20 obesity-related genes and RCC. For the discovery portion of the study, 63 tissue pairs of RCC tumors and normal adjacent tissues from the surrounding kidney were used. An additional 177 pairs were included for the validation component of the study.

The patients were mostly males with an average age of 59 years who had never smoked. Most of the patients had clear cell RCC and were at the earliest stage of disease.

“Patients were classified into high- and low-LEPR methylation groups,” said Julia Mendoza-Perez, Ph.D., a visiting scientist of Epidemiology at MD Anderson who presented the findings at AACR. “We found that high LEPR methylation was associated with a significantly higher risk of tumor recurrence.”

The results were adjusted by age, gender, pathologic stage of disease, grade, smoking status, body mass index, hypertension and histology.

“In addition, high LEPR methylation in tumors was associated with more advanced tumor features, such as high pathologic stage, high grade, and clear cell RCC histology,” said Wu.

The researchers add that future studies are needed to further understand the biology underlying the ties between LEPR methylation and RCC recurrence.