Every dog owner fears the day they might hear the word “cancer” from their vet. This devastating disease affects not only humans but our canine companions as well. Veterinary scientists and clinicians are now employing the same methods as researchers studying human cancer, bringing the tools of personalized cancer treatment and drug research and development to bear on canine cancer, and in the not-too-distant future the treatment for a dog’s cancer may become as personalized as the bond they share with their owner.
Developing and testing new drugs and therapies is crucial to improving cancer treatments for canines. One of the most powerful tools in the drug development toolbox is the bioassay. Bioassays enable scientists to measure the biological activity of a potential treatment compound to determine if it might be effective as a therapeutic agent. For researchers focused on advancing canine cancer therapies, bioassays are indispensable. They offer precise insights into how new drugs interact with cancer cells and the immune system.
Some of our most advanced medicines today rely on components derived from living organisms. These therapeutics, called biologics, include things like vaccines, blood products like Human Blood Clotting Factor VIII (FVIII), antibodies and stem cells. Biologics are incredibly temperature sensitive, which means they need to be kept cold during production, transport and storage, a process collectively called the cold chain. The stringent transport and storage temperature requirements for biologics create a barrier to accessing these lifesaving options; particularly for those in remote or underdeveloped regions, where maintaining a cold chain is logistically difficult and costly.
But what if we could break the cold chain? Inspired by one of the most resilient creatures on Earth – the tardigrade – scientists at the University of Wyoming are exploring ways to do just that.
Immunotherapy in veterinary medicine is a rapidly evolving field that leverages the immune system to fight diseases. These therapies are particularly effective in treating various cancers, including lymphomas, mast cell tumors, melanomas, and osteosarcomas. Beyond cancer, immunotherapies are also being explored for their potential in managing chronic inflammatory diseases, such as autoimmune disorders where the immune system mistakenly attacks the body’s own tissues. While traditionally, veterinary treatments have focused on surgery, chemotherapy, and radiation, the advent of immunotherapy offers a more targeted approach, particularly for conditions like cancer.
This targeted approach not only minimizes collateral damage to healthy tissues but also offers the potential for longer-lasting protection by training the immune system to recognize and fight off recurrence of the disease. The interest in immunotherapies has grown in tandem with advancements in human oncology, leading to a crossover of technologies and methodologies into veterinary applications.
Contraception, or birth control, is an important tool in family planning. Given the fourfold increase in population over the last century1 there is a clear need for more affordable, reversible, and safe methods of contraception. At present, the responsibility of takingcontraceptives falls largely on people with female reproductive organs as there is no current method of birth control for people with male reproductive organs. The search for a non-hormonal, male birth control has been an elusive goal in the field of reproductive health.
Recently, a group of scientists from Baylor College of Medicine with contributions from Promega scientists identified a novel compound that 1) inhibits a specific kinase and 2) functions as a reversible male contraceptive. The kinase targeted in this study is the serine/threonine kinase 33 (STK33); a genetic knockout of this gene in male mice is known to cause sterility. The team published their work in Science and utilized a suite of approaches—including DNA-Encoded Libraries (DELs), crystallography, and cellular NanoBRET™ Target Engagement Kinase Assays—to discover a potent inhibitor of STK33 (CDD-2807). The CDD-2807 inhibitor has shown promising results in inducing reversible contraception in male mice, marking a significant milestone in the development of non-hormonal contraceptive options. Let’s dive into the foundation, novel methodology, collaboration, and implications for this work.
At the American Association for Cancer Research meeting in April 2016, then Vice President of the United States, Joe Biden, revealed the Cancer Moonshot℠ initiative— a program with the goals of accelerating scientific discovery in cancer research, fostering greater collaboration among researchers, and improving the sharing of data (1,2). The Cancer Moonshot is part of the 21st Century Cures Act, which earmarked $1.8 billion for cancer-related initiatives over 7 years. The National Cancer Institute (NCI) and the Cancer Moonshot program have supported over 70 programs and consortia, and more than 250 research projects. According to the NCI, the initiative from 2017 to 2021 resulted in over 2,000 publications, 49 clinical trials and more than 30 patent filings. Additionally, the launch of trials.cancer.gov has made information about all cancer research trials accessible to anyone who needs it (3).
“We will build a future where the word ‘cancer’ loses its power.”
First Lady, Dr. Jill Biden
In February 2022, the Biden White House announced a plan to “supercharge the Cancer Moonshot as an essential effort of the Biden-Harris administration” (4). Biden noted in his address that, in the 25 years following the Nixon administration’s enactment of the National Cancer Act in 1971, significant strides were made in understanding cancer. It is now recognized not as a single disease, but as a collection comprising over 200 distinct diseases. This period also saw the development of new therapies and enhancements in diagnosis. However, despite a reduction in the cancer death rate by more than 25% over the past 25 years, cancer continues to be the second leading cause of death in the United States [4].
The Cancer Moonshot is a holistic attempt to improve access to information, support and patient experiences, while fostering the development of new therapeutics and research approaches to studying cancer. In this article, we will focus on research, diagnostics and drug discovery developments.
Solving for Undruggable Targets
KRAS , a member of the RAS family, has long been described as “undruggable” in large part because it is a small protein with a smooth surface that does not present many places for small molecule drugs to bind. The KRAS protein acts like an off/on switch depending upon whether it has GDP or GTP bound. KRAS mutations are associated with many cancers including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC). The G12 position in the protein is the most commonly mutated; G12C accounts for 13% of the mutations at this site, and is the predominant substitution found in NSCLC, while G12D is prevalent in PDAC (5).
In the evolving landscape of drug discovery, cyclic peptides represent an exciting opportunity. These compounds offer a unique balance of size and specificity that positions them to bridge the gap between small molecule drugs and larger biologics like antibodies.
However, most cyclic peptides demonstrate low oral bioavailability: they are digested in the stomach before they can enter the bloodstream, or they’re not absorbed into the bloodstream by the gastrointestinal tract and can have little therapeutic effect (1). Biologics face a similar challenge and are administered intravenously rather than with a more convenient pill form.
To address the challenge of low oral bioavailability of cyclic peptides, a team from the Ecole Polytechnique Fédérale de Lausanne in Switzerland developed a “one-pot” method to synthesize a diverse library of cyclic peptides, which they then screened for stability, activity and permeability (1). Their method, which was published December 2023 in NatureChemical Biology, streamlined the process of identifying and optimizing cyclic peptides and marked a substantial improvement from their earlier studies, where the developed cyclic peptides exhibited almost no oral bioavailability (%F). Using this new method, the team successfully developed a cyclic peptide with 18%F oral bioavailability in rats.
This blog covers the details of this study as well as a brief background on cyclic peptides.
Identifying Inflammasome Inhibitors: What’s Missing The NLRP3 inflammasome is implicated in a wide range of diseases. The ability to inhibit this protein complex could provide more precise, targeted relief to inflammatory disease sufferers than current broad-spectrum anti-inflammatory compounds, potentially without side effects.
Studies of NLRP3 inflammasome inhibitors have relied on cell-free assays using purified NLRP3. But cell-free assays cannot assess physical engagement of the inhibitor and target in the cellular micro-environment. Cell-free assays cannot show if an NLRP3 inhibitor enters the cell, binds the target and how long the inhibitor binding lasts.
Cell-based assays that interrogate the physical interaction of the NLRP3 target and inhibitor inside cells are needed.
When we think about the immune system, B cells and T cells are often the focus of attention. B cells are known for producing antibodies, and T cells are celebrated for their cytotoxic capabilities. More recently, however, macrophages are being brought into the spotlight and recognized for their integral role in immune defense and the field of biologic drug development.
On Thursday November 9th, 2023, Promega held its 7th Biologics Symposium at the Babraham Research Campus in Cambridge. For the first time, participants had the option to attend the event either in person or experience it via live stream, creating an inclusive and dynamic environment where the latest breakthroughs and ideas could be showcased. Moreover, the event was organized into a morning and afternoon session, enabling ample time for networking and the exchange of ideas beyond formal presentations.
It has been more than 100 years since Dr. William B. Coley, known today as the “Father of Immunotherapy,” made the first recorded attempt to mobilize the immune system as a means of treating cancer (9). Decades later, the discovery of T cells and the vital role they play in the immune system set the groundwork for many new immunotherapy treatments, such as those involving monoclonal antibodies, cytokines, CAR T cells, and checkpoint inhibitors.
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