Fetal cells reveal breast cancer secrets
Salk researchers find a ‘master control switch' for aggressive breast cancer
LA JOLLA, Calif.—Salk Institute professor Dr. Geoffrey Wahl has been busy of late—making the news around the campus, as well as in journals, on top of work showing how (and perhaps why) cells in breast cancers so resemble embryonic mammary stem cells.
The overall observation itself isn’t new. As Salk notes, Italian surgeon Francesco Durante—using a simple microscope—was struck more than a century ago by the similarities between cells found in very malignant cancers and the embryonic cells of the organ in which such cancers originate.
Now, Salk scientists believe they have revealed at least one reason for the uncanny likeness: cells in human basal-like breast cancers share features with the embryonic mammary (breast) stem cells that are the progenitors of all cell types in the mammary gland (of a mouse). The insights leading to this conclusion were published in the journal Cell Reports on Aug. 7.
“Durante was prescient,” said Wahl, holder of the Daniel and Martina Lewis Chair at Salk and senior author of the work. “He anticipated the relatedness of cells in the embryo to those in malignant cancers—and that dormant cancer cells could be ‘reawakened’ by exposure to ‘persistent irritations’ that we now recognize as inflammation. We can use the insights gained from our work to develop better diagnostic and treatment strategies.”
The very specific metabolic features that human breast cancer shares with early embryonic mammary stem cells, for example, may be possible to target therapeutically, and proteins specifically expressed in the embryonic cells that are also expressed in the cancers might lead to new diagnostic tools or immune therapies.
Wahl and his research group at Salk, along with investigator Dr. Benjamin Spike of the Huntsman Cancer Institute at the University of Utah, used cutting-edge techniques to generate an atlas of the genes expressed in each breast cell from very early in development until adulthood, a process that required an analysis of many thousands of cells. They used this “single-cell-transcriptome atlas” to compare genes expressed in human breast cancers. This led to an understanding of how the stem cells of the breast arise in early development and how they turn into the two different types of cells that comprise the mature gland.
“There has been intense interest in determining how rare cells in tumors can fuel tumor growth and resistance to therapies,” said Spike, who is an assistant professor of oncological sciences at the University of Utah and the paper’s co-corresponding author. “Much of the molecular machinery they use to do this appears to be co-opted and corrupted from stem cells and progenitors that used this machinery to build the normal tissue during development. Our study provides an atlas of the responsible genes that can be tested for their potential as therapeutic targets.”
“This work shows the diversity of ways that cells can enter the stem state, which is characterized by their plasticity, or developmental flexibility,” added first author Dr. Rajshekhar Giraddi, a Salk research associate in Wahl’s lab. “This suggests that cancer cells may gain their plasticity by many strategies, similar to those we are discovering in normal development.”
This plasticity means that there is—as has become pretty clear in cancer research over the decades—likely no single “silver bullet” that is going to definitively finish off any given cancer, much less something like aggressive breast cancer. But this newfound knowledge helps explain why the cells within a single tumor can appear so different from one another and may provide a key reason as to how malignant cancer cells become resistant to most therapies. Also, armed with new knowledge about the genetic signatures of different cell states, the lab is developing new ways of looking at the reprogramming of adult cells into states associated with cancer.
Other work out of the Wahl lab recently—published in the journal Cancer Cell on Aug. 30—includes findings that tie the gene Sox10 to breast cancer because of the gene’s role in the cellular reprogramming that seems to be the key to cancer’s ability to form new cell types, evolve drug resistance and metastasize to other locations in the body. In fact, Sox10 may be a bit of a ‘master switch’ in aggressive breast cancer.
According to the Salk Institute, this “represents a major milestone in researchers’ understanding of cancer and could open new avenues for diagnosing and treating aggressive breast cancer, as well as other types of intractable cancers.”
“Two things that make triple-negative breast cancers so hard to treat are their heterogeneity—they have many different cell types within a single tumor—and their ability to move around and colonize new areas, the process of metastasis,” explained Wahl. “It’s what you could call the imprecision in precision medicine, in the sense that we might target one type of cell, but there are other cells within the tumor that can change to become drug-resistant, analogous to how a chameleon changes colors to evade predators.”
Going back to the plasticity issue described earlier, the team notes that adults cells turn off the plasticity so critical in stem cells, which then later can get reawakened and turn cells cancerous.
“The embryo will supercharge certain cells to rapidly start critical developmental processes that spawn the growths of new tissues, but it’s very important that these cells get shut off when your body no longer needs this to occur,” says Dr. Christopher Dravis, a Salk staff scientist and the Cancer Cell paper’s co-first author. “In aggressive breast cancers, we’re finding that safety mechanisms that regulate these powerful development genetic programs are lost, so these processes underlying cellular plasticity are being reactivated to drive tumor development and ultimately the malignancy that’s associated with the disease.”
In this newer study, the Wahl lab began by examining which parts of mouse mammary cells’ DNA—which is tightly coiled in a package called chromatin—was uncoiling to make specific genes more accessible. This was the team’s first clue to which genes might be active during development. The chromatin analysis revealed that in both fetal cells and a subpopulation of breast tumor cells, the same areas of the genome were becoming accessible—areas where a master gene regulator called Sox10 is known to bind to DNA to initiate a variety of developmental processes.
“In fetal cells, which are the most ‘plastic,’ we saw that binding sites for Sox10 were very open and accessible compared to healthy adult cells, which are mostly inflexible and the chromatin is very closed,” notes Dr. Chi-Yeh Chung, a Salk research associate and the paper’s co-first author.
Next, the team showed that Sox10 actually bound to genes in the open regions to activate them, thereby directly regulating genes responsible for cell type, mobility and other features relevant to breast cancer’s ability to evolve and metastasize. Breast cancer cells with high levels of Sox10 changed to become much more primitive and acquired the ability to move. The results were so dramatic that the team repeated the experiment with a technique to keep Sox10 from binding to those genes. This time, without access to Sox10, none of the breast cells that had been programmed to turn cancerous were able to form tumors.
The researchers caution that while blocking Sox10 might be a useful strategy, methods to do so will require further development and will have to be tested for safety to determine if they impact normal cellular functions. However, the fact that Sox10 regulates many genes potentially linked to aggressive breast cancer offers the potential to target one or more of them as the basis for developing personalized therapies for metastatic breast cancer. Additionally, the findings could lead to diagnostic tests for breast and other cancers by checking adult tissues for proteins that normally would only be produced by fetal cells.
The team next plans to explore potential therapeutic drug targets among the genes regulated by Sox10.
Evaluating RX-5902 in combo with Keytruda for TNBC
ROCKVILLE, Md.—Rexahn Pharmaceuticals Inc., a clinical-stage biopharmaceutical company developing targeted therapeutics for the treatment of cancer, announced late August that it had entered into a clinical trial collaboration agreement with Merck & Co. (known as MSD outside the United States and Canada) to evaluate the combination of Rexahn’s RX-5902 and Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab), in a Phase 2 trial in patients with metastatic triple-negative breast cancer (TNBC).
“RX-5902 has both antitumor and immune-modulatory effects and augments the efficacy of checkpoint inhibitors in animal models,” said Dr. Peter D. Suzdak, CEO of Rexahn. “Based on the mechanism of action of RX-5902 and our observations in preclinical studies, we are optimistic that the combination of RX-5902 with Keytruda may provide meaningful clinical benefit in patients with metastatic triple negative breast cancer, a cancer that is notoriously difficult to treat.”
The study will evaluate the safety and efficacy of the combination of RX-5902 and Keytruda in patients with metastatic TNBC who have progressed following at least one prior treatment. Under the terms of the agreement, Rexahn will sponsor the RX-5902 and Keytruda study.
RX-5902 (supinoxin) is an orally administered, potential first-in-class, small-molecule inhibitor of phosphorylated-p68 (P-p68). P-p68, which is selectively overexpressed in cancer cells and is absent in normal tissue, modulates the activity of the β-catenin/Wnt pathway and plays a role in tumor progression, metastasis and tumor immunogenicity.
In preclinical studies, RX-5902 has been shown to inhibit the growth and proliferation of multiple human cancer cell lines (including triple-negative breast cancer), decrease tumor growth in patient-derived xenograft models and potentiate the activity of immune checkpoint inhibitors and other anti-tumor agents. RX-5902 is currently being evaluated as monotherapy in a Phase 2 clinical trial in patients with metastatic TNBC. Preliminary data was presented at the American Society for Clinical Oncology Annual Meeting in June 2018.
Oncolytics teams with SOLTI to examine pelareorep for breast cancer
CALGARY, Alberta & SAN DIEGO—September saw Oncolytics Biotech Inc., which is currently developing Reolysin (pelareorep) as an intravenously delivered immuno-oncolytic virus to turn “cold” tumors “hot,” announce a clinical collaboration with SOLTI, an academic research group dedicated to clinical and translational research in breast cancer. This clinical collaboration, being sponsored by Oncolytics and facilitated by SOLTI, is a window of opportunity study in the neoadjuvant setting for breast cancer. Patients will receive the appropriate standard of care for their cancer subtype, plus pelareorep with or without the anti-PD-L1 cancer immunotherapy atezolizumab (Tecentriq). Patients are biopsied on day one, followed immediately by treatment and a final biopsy after three weeks, on the day of their mastectomy. Data generated from this study is intended to confirm that the virus is acting as a novel immunotherapy and to provide comprehensive biomarker data by breast cancer subtype, to support Oncolytics’ Phase 3 study in metastatic breast cancer. The data in question is expected to be available in mid-2019.
“We expect that this study will provide additional biomarker and immunological data to support our planned Phase 3 study in metastatic breast cancer,” said Matt Coffey, president and CEO of Oncolytics Biotech. “This data should confirm the findings of our Phase 2 study and generate a robust biomarker plan designed to potentially enhance our Phase 3 program. Importantly, it will also generate additional data demonstrating how the promotion of a virally induced inflamed phenotype should synergize with checkpoint inhibitors targeting PD-L1 like atezolizumab.”
The study, facilitated by SOLTI, will be coordinated by Dr. Aleix Prat, head of medical oncology at the Hospital Clínic of Barcelona, associate professor at the University of Barcelona and the head of the translational genomics and targeted therapeutics in the Solid Tumors Group at August Pi i Sunyer Biomedical Research Institute. SOLTI has a network of more than 300 professionals, mostly medical oncologists, in over 80 hospitals in Spain, Portugal, France and Italy. Final study design and other details will be announced upon enrollment of the first patient, expected around the end of 2018 or very early 2019.
“It has been demonstrated that when reovirus infects a tumor, it promotes the release of immuno-stimulatory signals. This in turn results in the upregulation of PD-L1 on tumor cells and the recruitment of inflammatory immune cells like NK-cells and cytotoxic T-cells to the tumor, which are required prerequisites for checkpoint inhibitors to function effectively. In short, it turns cold tumors hot,” said Prat. “We believe pelareorep can demonstrate the necessary inflamed tumor phenotype to prime tumors for PD-L1 blockade, which could potentially represent a promising form of cancer immunotherapy combination with atezolizumab. Results from this study will seek to establish the virus as an important immuno-oncology agent in breast cancer, which could ultimately support the expansion of pelareorep beyond metastatic breast cancer into first-line therapy.”
Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class, intravenously delivered immuno-oncolytic virus being evaluated for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers.
BriaCell adds new clinical site to Phase 2a study
BERKELEY, Calif. & VANCOUVER, British Columbia—BriaCell Therapeutics Corp., an immuno-oncology biotech with a proprietary targeted immunotherapy technology, recently announced that the Cancer Center of Kansas (CCK) has been added as a new clinical trial site. BriaCell is currently conducting an ongoing, multicenter, Phase 2a study of Bria-IMT (listed in ClinicalTrials.gov as NCT03066947) in advanced breast cancer, as well as the rollover combination study of Bria-IMT with pembrolizumab or ipilimumab (listed in ClinicalTrials.gov as NCT03328026).
Dr. Shaker R. Dakhil will act as the clinical site’s principal investigator and will work closely with Cancer Insight LLC, BriaCell’s contract research organization, to manage the clinical and regulatory aspects of the Phase 2a clinical trial in advanced breast cancer on behalf of BriaCell.
“We are thrilled to be working with a leading oncology team at a well-respected center such as CCK, as we continue the clinical development of Bria-IMT in advanced breast cancer,” stated Bill Williams, BriaCell’s president and CEO. “We anticipate that multiple trial locations will provide treatment access to qualified patients in the U.S. Midwest. This new relationship should speed up the pace of recruiting for our Phase 2 clinical trial of Bria-IMT and the rollover study. Our top priority is to obtain data from these studies which will enable us to make Bria-IMT immunotherapy available to patients as soon as possible. We believe Bria-IMT is a safe and effective treatment. If data from the trial supports its effectiveness, Bria-IMT will fill a void in the treatment of advanced breast cancer, currently a huge unmet medical need."
Dakhil has served as president of CCK since 2000, and he is a clinical professor of medicine at the University of Kansas School of Medicine—Wichita, as well as serving as principal investigator for numerous cancer clinical trials.
Dakhil has led several earlier cancer research projects and was part of a three-physician team which developed the first implantable central venous catheter (known as port-a-cath), used in cancer care.
“Bria-IMT may represent a significant advance in the safe and effective treatment of advanced breast cancer patients,” commented Dakhil. “Early data from the preliminary trials and ongoing trials have been encouraging, and it is our hope they will be substantiated by these clinical studies at our site. We are excited to be working with the BriaCell team to make these treatments available to advanced breast cancer patients with poor survival prospects.”
The Phase 2a clinical trial of Bria-IMT and the Phase 1/2a rollover combination study with Keytruda and Yervoy in advanced breast cancer are currently being conducted at five top cancer centers: St. Joseph Health-Sonoma County, Santa Rosa, Calif.; Everett Clinic and Providence Regional Medical Center, Everett, Wash.; Jefferson Breast Care Center, Philadelphia; Sylvester Comprehensive Cancer Center, University of Miami in Miami; and Cancer Center of Kansas, Wichita.
Establishing a new standard of breast cancer care
LONDON & CAMBRIDGE, U.K.—This summer saw surgical guidance company Endomagnetics Ltd. announce that it had raised $10 million in Series C funding, led by Draper Esprit. This investment brings total funding for Endomag to over $22 million, and it will enable the company to significantly expand its capabilities, with the aim of treating more cancer patients around the world.
Endomag is pioneering the use of magnetic sensing for minimally invasive surgical guidance to ensure cancer can be targeted and removed more accurately. Their products address unmet clinical needs in availability, workflow efficiency and surgical accuracy to provide a better experience for patients with breast cancer. With this investment, the company can now focus on rapidly expanding its commercial activity in all markets and planned product development.
Dr. Eric Mayes, CEO at Endomag, said earlier in the year that: “2018 is shaping up to be the most significant year in Endomag’s history. Alongside securing this investment, we won a Queen’s Award for Enterprise in Innovation and received a 510K FDA clearance to extend the use of our Magseed magnetic marker—and it’s only July! This funding greatly increases our ability to scale in our primary markets and drive our continued growth.”
Lead investor Draper Esprit is the European division of the Draper Venture Network, founded by illustrious Silicon Valley venture capitalist Tim Draper, an early backer in companies such as Skype, Tesla and SpaceX. Draper Esprit’s investment in Endomag is, according to the company, a strong vote of confidence in the management team and the medical device company’s vision and future plans.
Vishal Gulati, Healthtech investor at Draper Esprit, commented: “We all know someone who has been affected by cancer, so having access to better cancer care benefits us all. Endomag is really kickstarting a revolution in how surgeons target the removal of tumors, something they’ve already demonstrated for breast cancer treatment. We’ve known about Endomag for a number of years and are excited to partner together.”
Since their inception in 2007, the team at Endomag has been applying their understanding of magnetic sensing technologies to develop products to help surgeons accurately locate and remove tumors as well as determine if the cancer has spread to other parts of the body. The company’s products have already been used in over 35,000 procedures across 300 hospitals in more than 30 countries.
Dr. Laura Esserman, director of the University of California San Francisco Carol Franc Buck Breast Care Center, said: “I’ve been a huge supporter of this technology for a long time. The Sentimag platform offers patient-centered products that dramatically improve the efficiency of localizing breast cancers and sentinel nodes. These tools provide a better patient experience, replacing a stressful procedure (wire placement in the breast the day of surgery) with a simple placement of a small clip in the week prior to surgery—not only is it better for patients, it is more accurate, safe and efficient.”
Synergistic enhancement of ozone therapy efficacy?
OCEANSIDE, Calif.—Therapeutic Solutions International Inc. announced in August the filing of a patent on recent data reportedly showing that pterostilbene potently augments killing of breast cancer, prostate cancer and ovarian cancer cells by ozone therapy.
The data are an extension of ongoing work at the company seeking to identify means of enhancing the effects of pterostilbene administration for treatment of a variety of cancers, as well as enhancing the efficacy of existing cancer therapies.
Previously the company had been granted United States Patent # 9,682,047 covering augmentation of immunotherapy efficacy using pterostilbene administration. Furthermore, the company has developed NanoStilbene, a nanotechnology-based product that enhances optimal delivery of pterostilbene to tissue. In the current patent application, administration of ozone in conjunction with various concentrations of pterostilbene resulted in enhanced tumor cell killing, without killing of control, non-cancer cells.
“The ability of ozone gas to possess a selective ability to kill cancer cells compared to non-cancer cells has been known since the 1980 publication by Sweet et. al. in the prestigious peer-reviewed journal Science. Furthermore, peer-reviewed studies have demonstrated that ozone therapy can enhance cancer-killing effects of chemotherapy,” said Timothy Dixon, president and CEO of Therapeutic Solutions. “By demonstrating potentiation of the cancer-killing effects of ozone therapy by pterostilbene, we anticipate initiating collaborations with international doctors studying the efficacy of this modality in the treatment of cancer.”
Therapeutic Solutions International has performed clinical pharmacokinetic studies using NanoStilbene to deliver pterostilbene. The concentrations of pterostilbene that are found in the blood four hours after oral administration of NanoStilbene are said to be sufficient to enhance the cancer-killing effect of ozone therapy, based on data presented in the patent application.
“Pterostilbene is known to kill cancer cells in part through increasing endoplasmic reticulum stress selectively in tumors and not in healthy cells. Our hypothesis was that ozone therapy may alter endoplasmic reticulum-associated molecular pathways, and thus a synergistic effect may be observed,” said Dr. James Veltmeyer, chief medical officer of the company. “By understanding molecular mechanisms of 'alternative medicines' such as ozone therapy, we can identify ways of leveraging their effects and developing therapeutic approaches that have higher chances of success.”
“Numerous physicians internationally are using ozone therapy and other means of oxidative medicine to treat chronic illness. Although techniques such as autohemotherapy have a very strong safety record, little work is being conducted at elucidating mechanisms of action and identifying ways of integrating these approaches into conventional cancer care,” added Dr. Juergen Winkler, a member of the company's scientific advisory board and medical director of Quantum Functional Medicine. “The medical doctors and scientists at Therapeutic Solutions International are leading the way in developing scientific understanding for molecular mechanisms of alternative medical immunotherapies in an objective and rigorous manner.”
