No need to call the fire brigade! The University of Dresden’s cancer sensor spots a mutation to p53, the most important cancer gene, and kills the cell.
Researchers at the University of Dresden, Germany, have developed a molecular sensor that detects a mutation in tumor protein p53 – implicated in 50% of cancers – and kills the cell. The research, published in Nature Communications, found that the sensor can detect mutations in p53 and kill the cell before it undergoes the cancer transformation process. Although the technology is at a very early stage, it could offer additional levels of protection against the development of cancer-causing mutations.
Cancer remains one of the biggest causes of mortality, with 8.8 million deaths recorded in 2015. Cancers evolve through natural selection, as mutations accumulate in oncogenes and tumor-suppressor genes over time. Strikingly, British researchers have recently shown that it can take as few as 10 mutations to cause cancer. For this reason, having a system in place to spot potential damaging mutations and prevent their spread to daughter cells could be a great way to get ahead of cancer.
The molecular “smoke detector” monitors p53, making sure that the gene is functioning as it should – binding DNA to stimulate the expression of p21, which controls cell division. The group designed a genetic element that makes the cell reliant on normal p53 function, which, if interrupted, initiates cell death. The researchers believe that this should suppress tumor formation at a very early stage.
With the technology firmly in the preclinical stages, a lot of work remains to be done. However, Frank Buchholz, Project Leader at University Hospital Carl Gustav Carus, is hopeful the technology could have a big impact: “The p53 sensor enables an active precocious intervention for the first time. Our results show that cells with p53 mutations can be selectively detected and eliminated at an early stage. Hence, the transformation process is prevented.”
p53 has been known about for a while now, with researchers and biotechs around the world devising plans to bring it back under control. Aprea Therapeutics is developing a drug to restore normal p53 function, which is being tested in a Phase II trial, while Orca Therapeutics has developed p53-expressing oncolytic viruses that rapidly eradicate tumors. Elsewhere, AstraZeneca and the Babraham Institute have improved our understanding of another cancer-causing gene, PTEN, which is highly implicated in breast and prostate cancers.
Looking forward, it will be interesting to see how clinicians decide who receives the p53 sensor if it can be developed for the market and whether the technology can be adapted for other genes like PTEN.
Images – Kateryna Kon / shutterstock.com; Meletios Verras / shutterstock.com
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Autolus has revealed a new strategy to treat T-cell lymphoma without harming healthy, protective T cells. The therapy is expected to start human tests soon.
T-cell lymphoma is a form of cancer that affects the cells responsible for protecting our body against infections. Unlike it’s done with cancer types that affect other blood cells, it’s not possible to just wipe all T-cells, which would leave the patient at the mercy of viruses and bacteria.
Autolus, a young biotech spun from University College London (UCL), wants to end this situation with a therapy that selectively removes cancerous T-cells while leaving enough healthy T-cells required for protection. In a study published today in Nature, researchers from Autolus and UCL detail their strategy and prove it works in mice.
The basis of Autolus approach is based on two subtypes of receptors that T-cells naturally produce, called TRBC1 and TRBC2. While healthy T-cells randomly express one of either, those affected by lymphoma always express only one of either in each patient. In the study, the researchers created CAR-T cells engineered to recognize and kill T-cells expressing TRBC1 in mice, which killed tumoral cells while sparing the portion of healthy T cells that expressed TRBC2.
This strategy is the basis of AUTO4, a CAR-T cell therapy being developed by Autolus. The company, which recently closed a big €68M Series C fundraising to boost its technology, expects the treatment to enter a first clinical trial in humans in the coming months. AUTO4 will be the fourth cancer therapy from Autolus to enter the clinic, and the first for T-cell lymphoma.
CAR-T cell therapies have been hailed as a “miracle cure” for cancer. However, the first ones, which were approved just this year, are directed at blood cancers affecting B-cells instead of T-cells. If successful, Autolus could bring the first effective therapy for T-cell lymphoma, for which current treatment options are not good enough. So much so that the US National Comprehensive Cancer Network (NCCN) recommends clinical trials as the preferred option after a first treatment for patients diagnosed with this form cancer.
Images via Christoph Burgstedt /Shutterstock; Autolus
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Update: Erytech has upgraded its projected IPO to $125M by offering more shares than originally planned.
Originally published 09/10/2017
Erytech has filed for an IPO on the Nasdaq Global Market and a private placement on Euronext Paris while preparing for its first product approval.
Erytech, based in Lyon, is developing a unique technology based on encapsulating drugs in red blood cells. The company has now announced the launch of a global offering to raise funds through an initial public offering of up to $100M (€85M) on the Nasdaq Global Market under the ticker “ERYP” and a private placement of shares, of an undisclosed amount, on Euronext Paris.
Both offerings seem to be timed with upcoming meetings with the FDA and the EMA’s CHMP to discuss the design of a Phase III study for its lead candidate, eryaspase, in pancreatic cancer. In addition, Erytech is preparing to resubmit for the European approval of eryaspase to treat relapsed or refractory acute lymphoblastic leukemia (ALL) after the first was withdrawn when the EMA requested additional data.
Erytech’s GRASPA, the commercial name for eryaspase in Europe and Israel, consists of the enzyme L-asparaginase encapsulated within donor-derived red blood cells. The enzyme depletes the amino acid asparagine from the bloodstream to starve the tumor cells that, unlike healthy cells, cannot produce their own asparagine. The treatment is under development to treat ALL, pancreatic cancer, acute myeloid leukemia (AML) and solid tumors.
Image via zhaoliang70 /Shutterstock
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Try as we might, we can’t cover all the biotech news out there! Here’s a roundup of news that didn’t make the cut this week.
- Allergan has returned development rights to Heptares for its muscarinic M1 agonist designed to treat Lewy body-based dementia.
- In a secret deal, Oxford BioDynamics has a new “major US pharma” partner.
- French spinout Dynacure licensed a drug for centronuclear myopathy from Ionis.
- Novartis is looking for EMA approval of Kymriah, its recently FDA-approved CAR-T therapy.
- Nordic Nanovector amended its protocol to continue with its Phase II trial for its mAb Betalutin in the UK.
- ReNeuron also received approval to move its retinal disease candidate forward into Phase II.
- Adaptimmune reported early-stage positive results for its SPEAR T-Cell therapy.
Images from Marco Diaz Segura, FACTORYPIC, Tilo G
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Until recently, cancer detection depended on invasive solid tissue sampling that didn’t provide a complete picture. These biotechs are making it easier to detect cancer early with liquid biopsies.
The notion that a person’s blood can reveal a wealth of health information looked so shiny that a company leading the charge, Theranos, was valued at $1B at its peak in 2014. Even though it has since come crashing down — the company recently listed its lab space for rent — efforts in the development of blood-based testing are going strong.
In particular, many companies are seeing success in the field of cancer diagnostics. “Oncology leads the way in blood diagnostics,” Dr. Ewan Hunter, Director of Business Development and Head of Statistics at Oxford BioDynamics, told me over the phone. His company analyses the environmental impact on the genome in the form of epigenetic DNA modifications. These modifications can then be used to screen for cancer, amongst other things.
Another company, QIAGEN, recently became the first to the European lung cancer market with its DNA-based technology: Therascreen enables VEGFR-based stratification of patients to determine if they are eligible for AstraZeneca’s Iressa. The product has since become the gold standard used in a majority of labs and clinics. Meanwhile, ANGLE has developed its own impressive test based on entire cells instead of fragments of DNA of dead cells, and it stands to become the new go-to for ovarian cancer.
So why did liquid biopsy development start in oncology? “The starting point to determine what’s possible is clinical need, and that’s currently personalizing care for people with cancer,” Andrew Newland, CEO of ANGLE, told me. Immuno-oncology therapies work for some but not all, and they’re expensive. “We have to ensure that the right patients receive the right therapy, and the way to do that is via liquid biopsy,” he continued.
Traditionally, testing is done with antibodies, but some cancers don’t have all the necessary surface markers, which the antibodies target to give a readout. Solid biopsies also have a major limitation: they can only be taken once, making it impossible to track progression over time. This is because tumors are heterogeneous and their genetic makeup changes over time, so the second sample won’t match the first. And if that’s not reason enough, solid biopsies are also highly invasive.
Liquid biopsies, on the other hand, can be done with a routine blood draw, and the technology has come so far that various tests are already on the market. Furthermore, these tests are at the forefront of the wave of personalized medicines. “We’re moving towards more targeted therapies by understanding molecular mechanisms,” said Michael Kazinski, Senior Director of Head of Global Product Management Sample Technologies at QIAGEN. And the best way to personalize a treatment in such a manner is to start with a liquid biopsy.
I talked to these leaders in the European space to hear about what their companies are doing the improve early cancer testing.
The Molecular Approach: Free Circulating DNA
QIAGEN began as a spin-out from the Heinrich Heine University in Düsseldorf with the aim of isolating nucleic acids. This core capability has been translated into technologies which allow identification via circulating DNA, whose primary use is in prenatal and oncological applications
QIAGEN became the first bring a diagnostic to the European market that uses them to stratify patients based on epithelial growth factor receptors, an important site of mutation in various cancers. Patients with mutations making for overactive EGFRs are eligible for treatment with AstraZeneca’s Iressa, an EGFR inhibitor.
“Liquid biopsy is nothing more than combining various technologies to identify biomarkers circulating in the blood and other body fluids, but it has the potential to revolutionize healthcare,” QIAGEN’s Michael Kazinski, told me. “What makes it amazing is its sheer accessibility.” Sampling a tumor might sound simple, but some cancers like those of the brain require drill holes into the skull.
This accessibility also makes it easier to catch the disease earlier and monitor patients and their disease progression. “When you can see a tumor on PET scans or other imaging technologies, for example, it’s already very late in cancer progression,” explained Kazinski. “If you can identify the disease earlier, especially if it has resistant mutations, you can adapt a therapy to a patient,” he elaborated. “You can make it much more effective that way, and you can keep repeating the process to monitor the treatment’s efficacy.”
The next step for QIAGEN is to bring NGS and bioinformatics into the mix: the company hopes it will help to parse huge amounts of data allowing researchers to find correlations between genes and disease onset or progression. In addition, QIAGEN has developed a full suite of solutions covering PCR and NGS based analysis of circulating RNA, exosomes, and CTCs. When I asked about stumbling blocks, Kazinski told me they depend on the application: “Is there a sufficient amount of DNA? Will the test be reimbursed? We’re working through them, indication by indication.”
Oxford BioDynamics goes a step further than direct DNA sequence analysis by looking at regulatory genome architecture — that is, expression and silencing of genes via epigenetic mechanisms, specifically the changes in structure-function of the 3D genome organization. The company’s CSO, Alexandre Akoulitchev, said that these biomarkers are increasingly recognized as being highly informative for patient stratification:“In many indications, particularly in oncology, we demonstrate a very high correlation between disease manifestation and the molecular regulatory systems, which are all reflected in the abnormal genome architecture.”
The company’s platform, EpiSwitch, monitors systemic abnormal epigenetic signatures that are found in the cells present in a blood sample of someone with a particular disease or pathology. Based on this, EpiSwitch can identify, validate and monitor epigenetic biomarkers known as ‘Chromosome Conformation Signatures’ that represent an individual’s state of genome regulation, including its gene expression, genetic risks, and even metabolic state.
Chromatin conformations can be used to effectively stratify patients, as a group of researchers at the Mayo Clinic successfully demonstrated in a group of melanoma patients. Using a noninvasive test based on chromatin conformation biomarkers, the team was able to determine if a patient had melanoma, from early to late stage, and discriminate these patients from healthy controls or patients with non-melanoma skin lesions.
When I asked Akoulitchev why epigenetics is the best approach with the dawn of cell-based technologies, he explained that the value of epigenetics is that, “these markers are reflective of responses to the environment, and looking at this is essential. Reading the genome architecture using EpiSwitch proves to be much less noisy compared to other biomarker modalities, which include continuous ranges of readouts and stochastic noise, thus making the data hideously complicated.”
Oxford BioDynamics is focusing on immuno-oncology for now, although the applications of EpiSwitch are broad, with oncological, neurological and autoimmune indications all on the table. Akoulitchev said, “We’re agnostic when it comes to which disease areas, treatments, and patient stratifications to advance with EpiSwitch.”
The Cellular Approach
ANGLE leverages its circulating tumor cell (CTC) technology in its first clinical application to detect ovarian cancer. Ovarian cancer is particularly tricky to diagnose and as a result, many women do not receive the treatment they need. In the United States alone, over 750,000 women each year are diagnosed with an abnormal pelvic mass. Of these, around 200,000 will have surgery to remove the pelvic mass, with around 10 percent of those having surgery will have ovarian cancer.
For a benign mass, the surgery is straightforward — a one-hour operation, often key-hole surgery, after which the patient can sometimes go home on the same day; but ovarian cancer has to be treated much more carefully. It requires open surgery — six hours on the table and perhaps a week of intensive care afterwards — and care not to spread the cancer to other parts of the body. Naturally, if there’s a chance a tumor is malignant, patients and doctors will opt for the latter as patients with ovarian cancer who do not receive this specialist care usually have a poor outcome.
ANGLE is working to implement its Parsortix system to detect ahead of surgery which patients have cancer and to help doctors make more informed decisions to ensure patients receive the specialist care they need.
So how does the Parsortix technology work? “ANGLE pioneers the collection of living cancer cells from patient blood for analysis,” Newland told me. Traditionally, liquid biopsies hinge on dead cancer cell fragments, CTDNA, which doesn’t provide any data on RNA or protein expression. “This approach has not worked to detect ovarian cancer,” commented Newland.
Alternative approaches evaluating proteins in the blood suffer from low specificity with a high number of false positives. He pointed to Austin-based Vermillion and its ovarian cancer test, OVA1, as an example: OVA1 relies on a protein called CA125 and only between one sixth and one fifth of its positives are true positives. This is because while Vermillion’s technology boasts a high sensitivity of 92%, its specificity is low — only 54% — and proteins like CA125 can be upregulated for benign reasons instead of cancer.
“They’re looking at byproducts, not the actual cancer itself,” explained Newland.
Compared to OVA1, ANGLE’s Parsortix assay has the potential to provide similar high sensitivity but with a much higher specificity, with low false positives. And now that ANGLE has acquired Axela, it can leverage the Canadian company’s technology to analyze up to 100 genes simultaneously in what’s called a “sample-to-answer” process to quickly obtain a diagnosis.
“Axela’s technology has similar utility to NGS but for a much lower price,” remarked Newland, citing $50 to $100 per run compared to the millions it costs to maintain and run one of Illumina’s machine. The alternative approach is to use PCR: this comes with a much lower cost but it’s limited on a practical basis to only about 8 genes per sample, which is not enough for key clinical applications. ANGLE’s new Axela platform can run 100 genes at a similar price to PCR.
The present challenge for ANGLE isn’t competitors, Newland told me. Indeed, ANGLE seems to have a friendly relationship with another liquid biopsy leader, QIAGEN, as they signed a co-marketing partnership in September this year. Rather the major focus for ANGLE is completing the necessary clinical studies and pushing forward to regulatory approval.
“We’re hoping to be the first-ever FDA-approved live cell liquid biopsy in cancer,” Newland said. The final step, a 400-patient trial with MD Anderson is expected to be completed by the end of Half 1 in 2018; if the results are positive, ANGLE is well-positioned for launch.
Thanks to all of the interviewees for patiently answering my questions! Which companies would you have added? Comment below!
Images via donfiore, Carl Dupont, Evgeniy Kalinovskiy, Christoph Bergstedt, Kateryna Kon, RAJ CREATIONZS / shutterstock.com
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Inbiomotion has published the results of a Phase III study looking at its MAFTest to personalized approaches to the disease. Inbiomotion, based in Barcelona’s biotech hub, works on a highly selective biomarker for breast cancer. A Phase III study demonstrated that …
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A new study concludes the majority of cancer drugs approved by the EMA between 2009 and 2013 weren’t backed by sufficient evidence that they are effective. A team of researchers from King’s College London and the London School of Economics …
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Transgene has announced the launch of Invir.IO, a new platform to help the design of new oncolytic viruses that modulate the cancer microenvironment. Transgene designs targeted immunotherapies for the treatment of cancer and infectious diseases. Their lead products include Pexa-Vec, an oncolytic …
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