Prostaglandin E1 Inhibits Leukemia Stem Cells Targeting leukemia stem cells in combination with standard chemotherapy may improve treatment for chronic myeloid leukemia

Two drugs, already approved for safe use in people, may be able to improve therapy for chronic myeloid leukemia (CML), a blood cancer that affects myeloid cells, according to results from a University of Iowa study in mice.

CML is a relatively common cancer. The American Cancer Society estimates that in 2017 there will be about 8,950 new cases and about 1,080 people will die of the disease.

In its initial, chronic stage, CML is relatively easy to treat. Drugs called tyrosine kinase inhibitors (TKIs) are generally successful at controlling the cancer. However, patients need to continue the expensive treatment for their lifetime. In some cases, even with that treatment, the cancer can progress to a more advanced stage that is no longer controlled.

One reason for this, explains Hai-Hui (Howard) Xue, MD, PhD, UI professor of microbiology and immunology, is that there are two kinds of tumor cells—bulk leukemia cells that can be killed by TKI drugs, and a subset of cells called leukemia stem cells, which are resistant to TKIs and to chemotherapy.

“A successful treatment is expected to kill the bulk leukemia cells and at the same time get rid of the leukemic stem cells. Potentially, that could lead to a cure,” says Xue, who is senior author of the study published in the September issue of the journal Cell Stem Cell as the cover story.

With that goal in mind, Xue and his team joined forces with Chen Zhao, MD, PhD, UI assistant professor of pathology, and used their understanding of CML genetics to look for small molecules or drug compounds that might be able to eradicate the leukemia stem cells.

Focusing on two proteins known as transcription factors, the researchers showed that genetically removing the two transcription factors, Tcf1 and Lef1, in mice is sufficient to prevent leukemia stem cells from persisting. Importantly, this genetic alteration did not affect normal hematopoietic (blood) stem cells.

Next the researchers used an informatics method called connectivity maps to identify drugs or small molecules that can replicate the gene expression pattern that occurs when the two transcription factors are removed. This screening test identified a drug called prostaglandin E1 (PGE1).

The team tested a combination of PGE1 and the TKI drug called imatinib in a mouse model of CML. The mice lived longer than control mice; 30 percent lived longer than 80 days compared to mice treated with only imatinib, all of which died within 60 days.

The team also looked at a different mouse model of CML, where human CML cells were transplanted into an immunocompromised mouse. When the mice received no treatment or were treated with imatinib alone, the human leukemia stem cells propagated and grew to relatively large numbers. In contrast, when the animals were treated with a combination of imatinib and PGE1, those numbers were greatly reduced, and mice did not develop leukemia.

“The results are a pleasant surprise,” says Xue who also is a member of Holden Comprehensive Cancer Center at the UI. “We do these kinds of genetic studies all the time—looking at transcription factors and what they do. This is a good opportunity to connect what we do at the bench to something that could be useful clinically.”

Investigating how the PGE1 works to suppress the leukemia stem cells, the team found that the effect relies on a critical interaction between PGE1 and its receptor EP4. They then tested the effect of a second drug molecule called misoprostol, which also interacts with EP4, and showed that misoprostol also has the ability to combine with TKI and significantly reduce the number of leukemia stem cells.

Both PGE1 and misoprostol are currently approved by the FDA for use in people. PGE1 is an injectable drug that is used to treat erectile dysfunction. Misoprostol is a pill that is used to treat ulcers.

“We would like to be able to test these compounds in a clinical trial,” Xue says. “If we could show that the combination of TKI with PGE1, or misoprostol, can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”

Sangamo Therapeutics and Pfizer Announce Collaboration for Hemophilia A Gene Therapy

Sangamo Therapeutics, Inc. and Pfizer Inc. announced this week, an exclusive, global collaboration and license agreement for the development and commercialization of gene therapy programs for Hemophilia A, including SB-525, one of Sangamo’s four lead product candidates, which Sangamo expects will enter the clinic this quarter.

“Sangamo brings deep scientific and technical expertise across multiple genomic platforms, and we look forward to working together to advance this potentially transformative treatment for patients living with Hemophilia A,” said Mikael Dolsten, MD, PhD, President of Worldwide Research and Development at Pfizer. “Pfizer has made significant investments in gene therapy over the last few years and we are building an industry-leading expertise in recombinant adeno-associated virus (rAAV) vector design and manufacturing. We believe SB-525 has the potential to be a best-in-class therapy that may provide patients with stable and durable levels of Factor VIII protein with a single administration treatment.”

“With a long-standing heritage in rare disease, including hemophilia, Pfizer is an ideal partner for our Hemophilia A program,” said Dr. Sandy Macrae, Sangamo’s Chief Executive Officer. “We believe Pfizer’s end-to-end gene therapy capabilities will enable comprehensive development and commercialization of SB-525, which could potentially benefit Hemophilia A patients around the world. This collaboration also marks an important milestone for Sangamo as we continue to make progress in the translation of our ground-breaking research into new genomic therapies to treat serious, genetically tractable diseases.”

Under the terms of the collaboration agreement, Sangamo will receive a $70 million upfront payment from Pfizer. Sangamo will be responsible for conducting the SB-525 Phase 1/2 clinical study and certain manufacturing activities. Pfizer will be operationally and financially responsible for subsequent research, development, manufacturing and commercialization activities for SB-525 and additional products, if any. Sangamo is eligible to receive potential milestone payments of up to $475 million, including up to $300 million for the development and commercialization of SB-525 and up to $175 million for additional Hemophilia A gene therapy product candidates that may be developed under the collaboration. Sangamo will also receive tiered double-digit royalties on net sales. Additionally, Sangamo will be collaborating with Pfizer on manufacturing and technical operations utilizing viral delivery vectors.

Gene therapy is a potentially transformational technology for patients, focused on highly specialized, one-time, treatments that address the root cause of diseases caused by genetic mutation. The technology involves introducing genetic material into the body to deliver a correct copy of a gene to a patient’s cells to compensate for a defective one. The genetic material can be delivered to the cells by a variety of means, most frequently using a viral vector such as rAAV. There have been no gene therapy products approved in the U.S. to date.

Hemophilia A is a rare blood disorder caused by a genetic mutation resulting in insufficient activity of Factor VIII, a blood clotting protein the body uses to stop bleeding. There are approximately 16,000 patients in the U.S. and more than 150,000 worldwide with Hemophilia A. SB-525 is comprised of a rAAV vector carrying a Factor VIII gene construct driven by a proprietary, synthetic, liver-specific promoter. The U.S. Food and Drug Administration has cleared initiation of human clinical trials for SB-525, which also has been granted orphan drug designation. Sangamo is on track this quarter to start a Phase 1/2 clinical trial to evaluate safety and to measure blood levels of Factor VIII protein and other efficacy endpoints.

 

Liver Disease Risk Increased by Type 2 Diabetes, Study Finds

People with type 2 diabetes are at greater risk of serious liver disease than those without the condition, research has shown.

Researchers warn that hospital admissions and deaths caused by liver disease are likely to rise if cases of type 2 diabetes continue to increase at current rates.

The team examined cases of liver diseases among people with diabetes from anonymised, securely linked hospital records and death records in Scotland over a ten year period.

They found that most cases of liver disease in people with type 2 diabetes are not alcohol-related but caused by a build-up of fat within liver cells – a condition known as non-alcoholic fatty liver disease or NAFLD.

NAFLD is commonly linked to obesity, which is also a risk factor for type 2 diabetes. Most people can avoid getting these conditions by following a healthy diet and taking regular exercise.

The research team – led by the Universities of Edinburgh and Southampton – found that men with type 2 diabetes are three times more likely to suffer from NAFLD than men without diabetes.

There are fewer cases of type 2 diabetes and liver disease amongst women but having type 2 diabetes increases the risk of NAFLD by five times, the study found.

People with NAFLD are more susceptible to the effects of alcohol on the liver and should avoid drinking to avoid further complications, the researchers say.

Treatment options for NAFLD – which increases the risk of life-threatening complications such as cirrhosis and liver cancer – are limited.

The study involved researchers from the Scottish and Southampton Diabetes and Liver Disease Group. It is published in the Journal of Hepatology and was funded by the Scottish Government through the Scottish Diabetes Group.

Professor Sarah Wild, of the University of Edinburgh’s Usher Institute for Population Health Sciences, said: “Preventing non-alcoholic fatty liver disease by avoiding unhealthy lifestyles in both people with and without diabetes is important because it is difficult to treat the complications of this condition.”

Professor Chris Byrne of the University of Southampton and University Hospital Southampton’s, NIHR Biomedical Research Centre said: “We have shown for the first time that type 2 diabetes is an important novel risk factor that increases numbers of hospital admissions and deaths, in people with all common chronic liver diseases. Further research is now needed to determine whether all patients with type 2 diabetes should be screened for common chronic liver diseases.”