At the recent American Association for Cancer Research (AACR) meeting, I had the pleasure of meeting several interesting young scientists and physicians either in the poster halls or in various scientific sessions. It seemed a great idea to encourage some of them to contribute some guess blog posts here on PSB.
Amongst the people I met was Dr Laura Strong, President and COO of Quintessence Biosciences.
One of the joys of social media is that sometimes you can get to know people a little from online interactions before you actually meet them in real life, making it much easier to walk up and introduce yourself as a ‘warm’ rather than ‘cold’ contact from a conversational standpoint. I’ve been following Laura (@scientre) for a while on Twitter and was keen to learn more about what her early stage biotech company does.
Quintessence Biosciences is, according to it’s website, “a biopharmaceutical company focused on development of novel protein-based therapeutics as anti-cancer agents. The Company’s products are based on the EVade™ Ribonuclease Technology which allows for the engineering of human proteins (ribonucleases) for the treatment of human diseases.”
Essentially, in plain English, this means that “The EVade™ Ribonucleases degrade ribonucleic acids (RNA), resulting in inhibition of protein synthesis and cell death.”
Laura was presenting a very interesting poster at the meeting, so I asked her if she was interested in writing a guest post about their work on RNases. She has most kindly agreed, so today and tomorrow we’re running a two-part mini series from Laura on RNases based on Quintessence’s work. For those interested in background research, you can check out more about the company here and also Laura’s blog, The Next Element.
RNases: From Concept to Clinic
At this year’s AACR Annual Meeting, I presented results from in vitro screening of combinations of our clinical stage ribonuclease (RNase). The theme of the meeting, Accelerating Science: Concept to Clinic, captures the serendipitous discovery that started on this course and subsequent development of this innovative and differentiated class of drugs.
Is RNA a good therapeutic target?
RNA has been a validated drug target for decades – from the discovery that various classes of antibiotics target ribosomal RNA to the more recent approaches using modified oligonucleotides to target specific RNA sequences. Vitravene is an oligonucleotide designed to binds a critical cytomegalovirus (CMV) messenger RNA that was approved by the FDA to treat CMV retinitis in immunocompromised patients. Recently a New Drug Application (NDA) was recently filed for another oligonucleotide drug, Kynamro (mipomersen sodium) that targets apolipoprotein-B to treat severe forms of familial hypercholesterolemia. These drugs have another feature in common: they do not target cancer.
In cancer drug development, the development of receptor tyrosine kinase inhibitors (TKIs) provides a potential roadmap for successful development of RNA-based therapies. While the early approved drugs, such as imatinib (targets bcr-abl to treat Philadelphia positive Chronic Myeloid Leukemia (CML)), provided significant benefit to patients, resistance via mutation in the ATP-binding pocket of the kinase domain has become a persistent problem in TKI therapy. This situation has prompted the development of second generation drugs (e.g. dasatinib and nilotinib for CML).
Another important lesson from TKI drug development is the clinical impact of targeting multiple and complementary aberrant signaling pathways. Even if the activity of one component of a pathway is blocked, there are often others that can compensate for the loss. In practice, this has led to development of pan-kinase inhibitors and to combining drugs in clinical trials based on the overlap of pathways. These results suggest that a single target approach may not have enough impact in targeting the RNA in cancer cells.
How do you go after multiple RNA targets?
One approach to target multiple RNA sequences inside a cell is to deliver multiple RNA drugs, such as modified oligonucleotides. Alnylam has taken this approach with their early clinical drug ALN-VSP. The drug uses small interfering RNA (siRNA), which are relatively short (1–22 base pair) RNA duplexes that inhibit messenger RNA once inside cells. In the case of ALN-VSP, two types of siRNA are included in a lipid nanoparticle. ALN-VSP targets two genes involved in liver cancer: kinesin spindle protein and vascular endothelial growth factor. The drug has completed a Phase I dose escalation study.
An alternative approach to attack multiple pieces of RNA in cancer cells is to use a human protein whose function is to degrade RNA, a ribonuclease (RNase). While this alternative may not be immediately obvious, serendipity played a role in bringing this concept to the clinic. In the late 1980s, frog egg extracts were screened for in vitro anti-cancer activity with positive results. The active component turned out to be a frog RNase that is part of the RNase A family.
Professor Ronald Raines at the University of Wisconsin made the connection that bovine RNase A, the prototypical family member, was not toxic to cancer cells and identified a major difference between the frog and bovine RNases. The bovine RNase A binds very tightly to the ribonuclease inhibitor protein found in the cytosol of human cells while the frog RNase does not. Using this information, a variety of bovine RNase A variants were produced with diminished binding to the inhibitor and these RNases were cytotoxic to cancer cells in vitro.
Using the closest human homolog, human RNase I, we first tested the concept of whether certain RNase variants may have anti-tumor activity in preclinical cancer models in mice. Forty human RNase I variants were produced based on data from a crystal structure data of the bound RNase and inhibitor and then tested in xenograft models. The RNases showed a range of activity, highlighting that the activity of the RNase is based on evasion of ribonuclease inhibitor but there are other factors, such as internalization and pharmacokinetics that also contribute to efficacy.
We selected QBI–139 as our lead candidate because the drug had the greatest activity across the most tumor types, including breast, colorectal, non-small cell lung, ovarian, prostate and pancreatic cancers. QBI–139 maintains 95% sequence identity to the human RNase I. The efficacy of QBI–139 was similar to chemotherapies and targeted agents when tested in preclinical models. We also did not see the common toxicities associated with chemotherapy (e.g. myelosuppression, alopecia, etc.) in the efficacy models.
The example shown is a xenograft model of prostate cancer (DU145) comparing QBI–139 to the standard of care agent docetaxel as well as the frog RNase. On a once weekly schedule, QBI–139 provides equivalent efficacy as the other two agents with less toxicity. At this dose, QBI–139 did not cause death (as in the docetaxel arm) or weight loss (as in the frog RNase treatment arm).
Do check back PSB tomorrow for the second part of Laura’s synopsis on RNases, which discusses the clinical aspects and where Quintessence are going with this interesting and novel concept.