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Wednesday, August 16, 2017

A study led by The University of Texas MD Anderson Cancer Center, Houston, has found a drug known as bone metastasis-targeting peptidomimetic (BMTP-11) has potential as a new therapeutic strategy for osteosarcoma (Proc Natl Acad Sci USA 2017; doi:10.1073/pnas.1704173114).

The preclinical study looked at BMTP-11 alone and in combination with the chemotherapy agent gemcitabine.

Although osteosarcoma is a relatively rare cancer, it is a leading disease-related cause of death in children and young adults ages 10 to 20. However, over the last 25 years, the 5-year survival rate has remained unchanged, and the treatment options for these patients are few. In addition, the side effects of available treatment options often are significant and cumulative, and may cause other health problems and damage to major organs.

"What's novel about this treatment is that BMTP -11 targets the tumor and spares other organs," said Valerae O. Lewis, MD, Chair of Orthopaedic Oncology at MD Anderson. "We believe this study lays the groundwork for a clinical trial for the treatment of osteosarcoma without the cumulative and mortal side effects seen with the current treatment options."

The study results identified IL-11Rα as an osteosarcoma cell surface receptor that correlated with tumor progression and poor prognosis in osteosarcoma patients. The team, which included co-authors Renata Pasqualini, PhD, and Wadih Arap, MD, PhD, both of whom worked on the study while at MD Anderson and are now professors at the University of New Mexico Health Sciences Center (UNMSC) School of Medicine, also illustrated that IL-11Rα and IL-11 are up-regulated in human metastatic osteosarcoma cell lines, and this correlated with the development of lung metastases in mouse models of the disease. The metastatic potential of the osteosarcoma cell lines could be modulated by targeting IL-11Rα expression. Death from respiratory failure linked to metastasis to the lungs remains a significant problem among osteosarcoma patients.

"We were able to document anti-tumor activity against osteosarcoma models," said Pasqualini. "Given that a first-in-human trial of BMTP-11 has recently been reported, one would hope that this proof-of-concept study might lead to early translational clinical trials in human osteosarcoma as a logical next step in the context of an unmet medical oncology need."

Arap added that "this work provides a preclinical foundation for the potential design and development of a second line combination therapy regimen composed of conventional chemotherapeutics plus the targeted candidate drug BMTP-11 for application in unfortunate patients with recalcitrant osteosarcoma."


Wednesday, August 16, 2017

Most women diagnosed with ovarian cancer undergo surgery to remove as many of the tumors as possible. However, it is usually impossible to eliminate all of the cancer cells because they have spread throughout the abdomen. Surgery is therefore followed by 18 weeks of chemotherapy.

Delivering chemotherapy drugs directly to the abdomen through a catheter offers better results than other methods, but this regimen suffers from significant complications, and many patients are unable to complete it.

MIT researchers who are working on an implantable device that could make intraperitoneal chemotherapy more bearable have published a new study that offers insight into how to improve chemotherapy strategies for ovarian cancer, and how to determine which patients would be most likely to benefit from this device (Gynecol Oncol 2017;146(1):161-169).

"As we entered into this project, our question was how do we get the same beneficial outcomes and reduce all the side effects?" said Michael Cima, PhD, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT's Koch Institute for Integrative Cancer Research, and the senior author of the study.

The findings suggest that the outcome of initial surgery plays a key role in the effectiveness of subsequent intraperitoneal chemotherapy. Cisplatin effectively treats very tiny tumor cell clusters when it is delivered continuously or as a single large dose. But the researchers found that, for larger tumor cell clusters, continuous delivery of cisplatin at higher doses than are tolerable with the current periodic chemotherapy method was more effective. The device they are developing would make delivery of such higher, continuous doses possible.

Targeting Residual Tumors

Ovarian cancer is usually not detected until the cancer has reached an advanced stage, with metastases covering organs throughout the peritoneal cavity, including the liver, bladder, and intestines. After tumor debulking, patients receive two types of chemotherapy to treat tumors left behind: IV delivery of paclitaxel and IV or intraperitoneal delivery of a platinum drug such as cisplatin.

Intraperitoneal chemotherapy is pumped directly into the abdomen through a catheter every 3 weeks for a total of six cycles. This allows cisplatin to come in direct contact with the residual tumors, which has been shown to be more effective than IV delivery, but is not tolerable for many patients. "It's painful and the catheter can be a site of local infections," Cima noted.

Several years ago, Cima and colleagues set out to develop an implantable device that could deliver cisplatin into the abdomen without all of the side effects produced by the catheter and the large, repeated cisplatin doses.

Their device is made of a drug-loaded polymer that could be inserted at the beginning of treatment and remain in place for the full treatment course, then removed with minimally-invasive surgery. The researchers have tested proof-of-concept devices in mice and are now developing a version that could be tested in humans, though more animal studies are needed before human trials can begin.

In their new study, the researchers set out to investigate how the size of the residual tumors would affect their response to continuous, low-dose cisplatin delivery. They believed that size would play some role because, once tumors reach a certain size, the drug may not be able to penetrate all the way into the inner core of the tumors.

To test this hypothesis, the researchers grew spherical ovarian cancer cell clusters 100 or 200 microns in diameter in a lab dish and exposed them to varying doses of cisplatin. Continuous, low-dose cisplatin delivery, similar to what tumors would receive from an implanted device, was as effective against 100-micron tumor spheroids as a single high dose, similar to that delivered by a catheter.

However, by increasing the continuous cisplatin dose, the researchers found they could treat the larger 200-micron spheroids more effectively than they could with the single high dose. This increased dose could be delivered using an implantable device, but it would not be tolerable for patients if given through an abdominal catheter.​

Improved Treatment Strategies

Cima believes the findings may also help explain some of the preliminary results of a recent, large clinical trial in which doctors found that intraperitoneal cisplatin delivery was no more effective than IV chemotherapy alone. This contradicted previous findings from smaller studies, indicating that cisplatin delivery by catheter improved patient survival.

In the newer trial, conducted at about 500 treatment centers, surgeons admitted patients to the study based on size estimates of the tumors remaining after surgery. However, Cima said, this subjective evaluation may have resulted in patients entering the study whose tumors were too large to be helped by the current intraperitoneal therapy.

This points to the importance of both developing a good method for screening patients before future trials begin to make sure they are likely to benefit from the treatment, and devising new strategies to help surgeons remove as many tumors as possible, Cima concluded.


Wednesday, August 16, 2017

By Heather Lindsey

Retrospective studies in women with advanced ovarian cancer have shown improved survival in those who are current and past users of nonselective beta-blockers.

In a recent feasibility trial, researchers determined that adding nonselective beta-blockers to intraperitoneal (IP) or IV chemotherapy in women with primary peritoneal (EOC) cancer is safe (Gynecol Oncol 2017; http://dx.doi.org/10.1016/j.ygyno.2017.03.058).

The combination could also benefit patients, although more research is needed, said lead study author Premal H. Thaker, MD, MS, Associate Professor of Obstetrics and Gynecology in the Division of Gynecologic Oncology at Washington University School of Medicine in St. Louis. She and her colleagues observed recurrence and mortality rates that were "encouraging based on the typical recurrence and mortality rates for this disease." 

Based on this study, nonselective beta-blockers appear safe during primary chemotherapy, commented Kevin Holcomb, MD, Director of Gynecologic Oncology at Weill Cornell Medicine and NewYork-Presbyterian Hospital.

Study Details

Thaker and her colleagues conducted a prospective study of patients who were started on 40 mg twice daily of oral propranolol 2-3 days before surgery. After intraoperative confirmation of disease, patients were again started on propranolol. It was given with the treating oncologist's choice of standard chemotherapy for 6 cycles. Patients were weaned off the study drug after completion of chemotherapy.

Of 84 enrolled patients, 35 had confirmed EOC and continued taking propranolol.

"Of the 25 evaluable patients, 22 could tolerate the dose that we started them on," said Thaker. Three patients needed a reduced dose of propranolol after the first round of chemotherapy because of hypotension. 

 Twenty-five women completed propranolol along with 6 cycles of IP (n = 13), dose-dense IV (n= 7), and every 3-week IV chemotherapy (n = 5). Four patients received bevacizumab. One patient was only able to complete 4 cycles of IV chemotherapy

During a 5-year follow-up period, seven patients did not experience a cancer recurrence, 10 have recurrent disease, and eight have died, Thaker reported. 

The researchers also conducted a multiplex analysis of 23 cytokines. Compared to baseline blood samples, they observed substantial reductions in circulating proangiogenic molecules, for example, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), interleukin 8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1).

A Well-Tolerated Drug

Propranolol, which is commonly given for blood pressure, problems with heart rate, and migraine, is typically well-tolerated, although rebound tachycardia and hypotension can be side effects, noted Thaker.

In the study, fatigue was common in patients, although whether this side effect was because of the propranolol, the chemotherapy, or having recently undergone surgery is unknown, she explained. Other potential side effects of propranolol include nausea, vomiting, diarrhea, constipation, and stomach cramps, according to Holcomb.

Drug Mechanisms

What propranolol mechanisms are benefiting patients "is the million-dollar question," said Thaker. She and her colleagues are still sifting through data from blood and tumor samples taken at several time points during the study; however, she theorizes that the drug may work through antiangiogenic and anti-inflammatory pathways. Specifically, VEGF and IL-6 and IL-8 may play a role in deterring cancer growth.

Holcomb noted that psychosocial stress results in the release of catecholamines from the adrenal gland, including noradrenaline and adrenaline. "These substances have been shown to impede the host immune response, increase tumor cell migration and invasion, and increase the release of proangiogenic factors," he said. "Non-selective beta-blockers have been shown to block these negative effects of the stress response in preclinical models."

Strengths & Limitations

One study strength is that it was a prospective trial with various chemotherapy routes, noted Thaker. Researchers observed tolerability across IP as well as IV chemotherapy, weekly or every 3 weeks. "We also have strong translational correlates," she said, referring to the blood and tumor samples that are giving researchers insight into the tumor microenvironment.  

However, one limitation of the study is that it included a small number of patients from a single institution, Holcomb said.​

Future Research

Thaker would like to see studies exploring whether propranolol is an economical and practical drug to give patients. She would also like to see randomized trials of the drug with chemotherapy and potentially as a maintenance therapy.

Other research has shown that propranolol may deter other cancer types such as sarcoma, melanoma, and breast cancer, "So this may be something that is pertinent not just to ovarian cancer patients, but can also work in other disease sites," she said.

"A prospective randomized evaluation of non-selective beta-blockers in women with advanced ovarian cancer with survival as the primary endpoint will be required to definitively determine the impact of this intervention," concluded Holcomb. In keeping with the goal of individualized cancer treatment, future studies need to stratify the various histologic and molecular types of ovarian cancer, he added.

Heather Lindsey is a contributing writer.


Wednesday, August 16, 2017

A new study of non-diabetic women with ovarian cancer reveals a potential correlation and area for further study regarding the expression of the GLUT1 glucose transporter receptor at the cancer tissue level (J Cell Physiol 2017; doi:10.1002/jcp.26023).

GLUT1 is a receptor protein involved in the absorption of glucose in the bloodstream and across membranes in the body. Physiologically, GLUT1 is not traceable in the ovaries. However, in patients diagnosed with ovarian cancer, use of immunohistochemical methods revealed the presence of this receptor, which tends to be intensely expressed in the most aggressive cases.

"Ovarian cancer is the leading cause of death among gynecological cancers. Despite remarkable achievements in terms of diagnoses and therapeutics, patient outcomes in terms of survival rates have remained largely unchanged. This is largely due to our limited understanding of the underlying mechanisms and pathways," said Maddalena Barba, PhD, researcher at the IRCCS Regina Elena National Cancer Institute of Rome, Central Italy.

"This study revealed a higher expression of the glucose transporter 1 in cancer samples of patients with lower glucose levels in non-diabetic women. These findings provide evidence in support of our prior results from this same study population. Indeed, we have recently observed an association between cancer stage at diagnosis and circulating levels of fasting glucose," explained Patrizia Vici, MD, clinical researcher at the Division of Medical Oncology 2 of the IRCCS Regina Elena National Cancer Institute.

The study included 40 randomly-selected patients from a larger cohort of 147 women diagnosed with high-grade, advanced-stage ovarian cancer.

"The findings from the immunohistochemical assessment of this population are key to understanding a variety of factors and determinants related to glucose metabolism in ovarian cancer. In addition, our findings establish a link between fasting glucose, and the expression of the glucose transporter GLUT1. We thus provide support to the hypothesis stated in our prior work within this same pipeline and, at the same time, ascertain the existence of a relation between a systemic and a local tissue biomarker related to energy metabolism. If confirmed in future studies, this may translate into the identification and characterization of innovative drug targets in ovarian cancer patients," concluded Antonio Giordano, MD, PhD, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia.​


Tuesday, August 15, 2017

A new study indicates that the customary pembrolizumab dose for treatment of metastatic non-small cell lung cancer (NSCLC) may be higher than is needed for effective treatment.

In October 2016, pembrolizumab became the new standard of care for first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 in at least 50 percent of cells.

The standard dosage for pembrolizumab was based on the KEYNOTE 024 trial. The dosage used in the trial was 200 mg for all patients (fixed dosing) every 3 weeks. As a result, this was the dose recommended by the FDA. Multiple studies have demonstrated equivalent efficacy with lower weight-based doses (personalized dosing), however. The objective of this study was to compare the economic impact of using personalized dosing (2 mg/kg) versus fixed dosing (200 mg).

Researchers suspected that using the FDA-approved dose of 200 mg for all patients may be an unnecessarily high dose, given that the average weight in the U.S. is 82 kg. In an era of value-based cancer care, avoidance of drug wastage is of paramount importance. If dosed at 2 mg/kg, an appropriate dose for the average American adult would be 164 mg.

Investigators performed a budget impact analysis to compare fixed dosing with personalized. They calculated the target population and weight of patients who would be treated with pembrolizumab annually. Using survival curves they estimated the mean number of cycles that patients would receive. Using the Medicare average sales price, researchers calculated the difference in cost between personalized and fixed dosing.

The results of the study indicated that the total annual cost of pembrolizumab with fixed dosing is $3.4 billion, but with personalized dosing it would be $2.6 billion. The use of personalized dosing would likely lead to a 24.0 percent annual savings, some $825 million, according to researchers.​