Mirati is striving to bring cutting edge science to the forefront. At this year’s meeting, among other research, we are proud to present our first clinical data set on central nervous system (or CNS) activity in patients with NSCLC harboring a KRASG12C mutation. This is important because CNS metastases can occur in up to 42% of patients with non-small cell lung cancer harboring the KRASG12C mutation, and often contribute or lead to death, posing a serious clinical challenge. I’m energized by what our team is doing to address this significant unmet medical need.
Most importantly, we want to thank the patients and physicians who make the research possible. I’m grateful to the dedicated Mirati Team who remain relentless in their pursuit of helping people living with cancer, who are counting on us to make a difference in their lives.
The groundbreaking research enabling the targeting of oncogenic drivers, including targets like KRAS which have been challenging for decades, have driven the development of the next generation of cancer medicines but also captured the interest of oncology researchers around the world, including Mirati Therapeutics and many biotech companies within the local San Diego area. Last week, I was fortunate to speak to these advancements and emerging opportunities in personalized cancer treatments at the 17th UC San Diego Moores Cancer Center Industry/Academia Next Generation Precision Oncology Symposium.
During the one-day symposium, researchers gathered to share the latest advancements in precision oncology to further progress this area of research and provide hope for those with cancer and their loved ones. This forum was designed to foster an open discussion of scientific and medical advances while placing an emphasis on the utility of using unpublished research to accelerate data dissemination.
Hosted by UC San Diego Moores Cancer Center, this valuable knowledge exchange is another example of why San Diego has become a hub for cutting-edge science within the biopharma industry and for those who seek to push the boundaries of health care investigation. I was inspired by the progress in precision oncology treatments and the collaboration from the symposium’s participants who shared new insights on targeted treatments, immuno-oncology, biomarker testing and emerging therapeutic strategies.
At the symposium, I provided an update on Mirati’s KRAS oncology pipeline contributing to the latest cancer research showcased at the event. The complex role of KRAS mutations in the pathogenesis of colon cancer and the potential of targeting the KRAS signaling pathway through therapeutic intervention was central to the theme of the symposium. KRAS mutations have been the focus of scientific research for more than 30 years, culminating in the discovery of a KRAS binding pocket enabling the development of KRAS targeted therapies.1 This discovery has driven Mirati’s drug development program for KRAS targeted therapies, inhibiting KRASG12C as well as opportunities to target other KRAS mutant variants and other challenging drug targets.
At Mirati, we have always believed in innovation through collaboration to provide meaningful breakthroughs for patients with hard-to-treat cancers. It was an honor to discuss Mirati’s advancements in KRAS targeted therapies and the latest research occurring within the local San Diego community at this year’s symposium. I look forward to further exploring the future of targeted oncology as we seek to improve the lives of those with cancer.
Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785.
Sometimes however, a mutation can occur in one of these “genomic guardian” genes that partially degrades the cell’s ability to repair mutational damage. Such genes are sometimes called “tumor suppressor” genes because when they function normally, they prevent the development of tumors. Often, a mutation that inactivates one of these tumor suppressor genes is on the road to becoming a cancer cell, allowing the cell to accumulate more mutations in other genes, leading to the unrestrained growth and division that characterizes cancer. Cancer, then, can be thought of as a disease of genetic instability.
In recent years, with greater understanding of the many molecular events that result in the transformation of normal cells into cancer cells, therapies have been developed that target specific “driver” mutations. A good example is the G12C mutation in the KRAS gene – a key “on/off” switch that controls the circuitry of cell growth and division in response to cellular signals. While the normal KRAS protein can switch the circuit on and off depending on the signals it receives, mutations like G12C cause the protein to become stuck in the “on” position, constantly signaling the cell to replicate and grow. Cancers that are driven by the G12C mutation are a key focus for Mirati’s research. KRASG12C inhibitors can be thought of as the contrast to chemotherapy, and an example of personalized or precision medicine – a therapy designed to work only in the subset of cancers that have the KRASG12C mutation.
Many cancer driver mutations have been identified with most of them, which can be targeted, having newer generations of “precision” cancer medicines. However, there is another approach to precision or personalized medicine that also exploits the cancer cell’s genetic instability, while more efficiently sparing normal cells. Organisms often evolve redundancies in the metabolic pathways involved in critical functions (such as DNA damage repair) that if the function of one gene is lost, another can compensate and maintain cell viability. In contrast, cancer cells develop inactivating mutations (or outright deletions) in one or more of these functionally redundant genes, rendering the tumor cell entirely dependent on the remaining “active” gene. By targeting the product of that last remaining gene, a drug can potentially be lethal to a cancer cell while sparing normal cells in which the “back-up” is still functional. This is the concept behind “synthetic lethality.”
The quintessential example of therapies designed to exploit synthetic lethality are the PARP inhibitors. PARP is an enzyme involved in the repair of single strand breaks in DNA. When PARP is inhibited, these single strand breaks accumulate and eventually become double-stranded breaks, affecting the DNA double helix. Cells with double-stranded breaks become dependent on other DNA damage repair pathways such as the homologous recombination pathway mediated by the tumor suppressor genes BRCA1 or BRCA2. Hence, breast, ovarian or prostate tumors with mutated BRCA genes are uniquely susceptible to PARP inhibitors as the combined inhibition of PARP with loss of BRCA activity eventually leading to catastrophic damage to the tumor DNA.
Another example of this synthetic lethality approach to cancer therapy is Mirati’s PRMT5 program. PRMT5 is a critical enzyme known as a “methyltransferase” that is involved in a host of essential cellular functions. Another enzyme called methylthioadenosine phosphorylase (MTAP) plays a critical role in methionine metabolism and is often missing in cancer cells because of its chromosomal location close to a commonly deleted tumor suppressor gene (CDKN2A).
Loss of MTAP in a cancer cell causes the accumulation of an intermediate called methythioadenosine, or ‘MTA.’ MTA is a partial inhibitor of PRMT5, therefore MTAP-deleted cells are profoundly sensitive to further inhibition of PRMT5 thereby setting up the context of vulnerability to synthetic lethality. This enhanced sensitivity to PRMT5 inhibition creates a large “therapeutic window,” in which doses of an inhibitor that are harmless to normal, MTAP positive cells, are lethal to MTAP-deleted cancer cells. Mirati’s PRMT5 inhibitor is designed to selectively bind PRMT5 in MTAP-deleted cancer cells in a novel way, and positioned to potentially have an improved therapeutic index based on the concept of synthetic lethality.
As is the case for inhibitors of G12C mutant KRAS tumors or PARP inhibitors in BRCA mutated cancers, a PRMT5 inhibitor drug is effective only in tumors with a homozygous MTAP deletion – which occurs in about 10 percent of all human cancers. This is another example of a ‘personalized’ or ‘precision’ approach to therapy that will only be active in an identifiable subset of cancer patients.
The promise of delivering on personalized medicine relies on suitable diagnostic tests (i.e. companion diagnostics) to identify patients who may benefit from targeted therapy. This is an important area of focus at Mirati and of the Translational Medicine team.
“We are purposefully building a collaborative team to tackle the problem of understanding and treating cancer head on,” says Jamie Christensen, chief scientific officer, Mirati Therapeutics, Inc. “Bringing together unique skillsets across translational research and discovery science, we are exclusively and aggressively focused on programs where existing interventions are unknown or insufficient.”
From seating charts to lab configurations, we are aspiring to maximize collaboration, curiosity, and our drive to do more for patients.
“We have an open office setting providing an opportunity to intermingle different functions and teams,” says Jamie. “Our labs are set up to be integrated so that all disciplines in R&D can benefit from one another and help rapidly share ideas.”
The Mirati culture is designed to unleash the potential of our science and our people by creating an environment that fosters open-mindedness and collaboration as we seek to transform the lives of patients with cancer. The company’s more than 320 employees are uniformly focused on patients by trying to make a difference with our science and in our communities.
“Where we differentiate ourselves is that we believe in advancing innovative oncology medicines focused on areas with significant unmet needs. Our portfolio is built on what is right in front us – we simply accept the challenge,” says Jamie. “The goal is to do things in a way that will help solve specific problems for identifiable patients by targeting the genetic and immunological drivers of cancer.”
Kelly Covello, head of Medical Affairs, shares a behind-the-scenes glimpse into the dynamic work of the Mirati Medical Affairs team and how their work intersects with patients, patient advocacy groups and healthcare professionals.
“At our core, every drug discovery scientist is an inventor,” reflected Matt Marx, senior vice president of Drug Discovery, in discussing the role of his team within Mirati.
Mirati’s Drug Discovery team comprises a variety of chemists–organic, medicinal, protein, protein crystallographers and computational chemists–who are responsible for the creation and identification of new molecules with the potential to become drug candidates.
The spirit of invention and forward-thinking unites the group, as the road between discovery project initiation and investigational new drug (IND) filing is arduous. The discovery engine can run 4 years or more on a single project and can often require the creation of hundreds to thousands of unique compounds before identifying one with the desired properties to move forward. Following this phase of discovery, a partnership between the Drug Discovery, Research, Drug Metabolism and early Development teams rigorously examines each potential lead molecule to understand whether it has the optimal characteristics for continued advancement toward filing an IND and entering clinical development. For the Drug Discovery team, the thrill of bringing forth new IND candidates that have the potential to benefit patients fuels their ongoing efforts.
“What started as a team with one employee 6 years ago has grown into a strong organization comprising veteran drug discovery scientists with strong and diverse talents,” said Matt. “The continuous and open feedback Mirati receives from patients ensures the patient experience remains at the forefront, centering our team’s focus on harnessing scientific discovery with a goal of advancing molecules with the potential to become meaningful medicines for patients.”
Mirati has a portfolio of innovation. The discovery of investigational KRAS (G12C and G12D) inhibitors and more recently the synthetic lethal PRMT5 program reinforce the strength of Mirati’s internal discovery capabilities.
“We will always approach our drug discovery research with cutting-edge innovation,” Matt concluded. “Guided by data, Mirati researchers are tackling cancer head-on to advance the next generation of targeted therapies.”
As a scientist, I have a unique opportunity to participate in advancing targeted oncology into a meaningful and highly impactful area of scientific development. Today, there are more than 50 FDA-approved targeted drugs for cancers with known driver mutations, and research advances are rapidly increasing the options to target cancer mutations.2
One important first step in identifying cancer drug targets and developing targeted therapies is to understand the underlying genetic basis of cancer causation and progression at a molecular and cellular level. The genomic era in cancer research has ushered in a principle called “oncogene addiction.” Oncogene addiction is defined by the dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties, despite the presence of multiple mutations that contribute to tumor progression.3 In other words, we are trying to identify a cancer drug target gene or protein that acts as the Achilles’ heel of each cancer. Some targets are more difficult to drug than others–it took close to 4 decades from the initial discovery of KRAS before the first drug candidate showed promising clinical efficacy in a subset of patients with KRAS-mutated cancers.4 This showed us that, while difficult, targeting KRAS wasn’t impossible.
At Mirati, our scientific discovery and preclinical research seeks to understand the KRASG12C mutation on a holistic level with the purpose of better understanding its pathway, lifecycle and potential resistance mechanisms. These insights have informed our initial drug design strategy and will continue to influence our clinical development strategy toward optimizing the potential clinical benefit to patients. Our research in KRASG12C has also led to important and exciting learnings in other areas of KRAS, including KRASG12D. Our science-driven focus on drug discovery and development is based on the principle that all aspects of the mutation and cancer biology need to be understood and targeted with precision.
The targeted oncology landscape is rapidly evolving, and the development of these therapies has dramatically changed the way we approach discovery and research.2 There is still much more to address, including drug resistance mechanisms and finding better sequential therapies or combination.
In many ways, oncology research and development is leading the way toward the promise of patient-centric, personalized medicines, and I anticipate we will be at the forefront of this research with the goal of developing targeted therapies across many difficult to treat cancer mutations.
Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785.
Ledford, Heidi. “Cancer: The Ras renaissance.” Nature 520.7547 (2015): 278-280.
Matikas, Alexios et al. “Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity.” Crit Rev Oncol Hematol 110 (2017): 1-12.
Ostrem, Jonathan M., Shokat, Kevan M. “Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.” Nat Rev Drug Discov 15.11 (2016): 771-785.
Bos, Johannes L. “ras oncogenes in human cancer: a review.” Cancer Res 49.17 (1989): 4682-4689
Simanshu, Dhirendra K. et al. “RAS proteins and their regulators in human disease.” Cell 170.1 (2017): 17-33.
Beganoyic S. CLINICAL SIGNIFICANCE OF THE KRAS MUTATION. Bosn J Basic Med Sci. 2009;9(Suppl 1):S17-S20.
Mirati estimates based on epidemiology data reported in Globocan 2022 (accessed 2019) and frequencies by mutation; Europe includes EU, Russia and 10 additional European countries; RET estimate does not include thyroid cancer. Rounded to the nearest 1,000.
Zehir A et al, Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703-713”
Campbell et al, Nature Genetics 2016 “Distinct patterns of somatic genome alterations in lung adenocarcinomas”
Bailey P et al, Nature 2016 “Genomic analyses identify molecular subtypes of pancreatic cancer”
Hallin J. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discovery, 2019.
Mirati Therapeutics. Data on File.
Percent et al. Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE). Journal of Clinical Oncology 2020 38:15_suppl, TPS9635-TPS9635.
Pircher et al., Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints. Int J Mol Sci, 2017. 18(11).
Akalu, Y.T., C.V. Rothlin, and S. Ghosh, TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev, 2017. 276(1): p. 165-177.
Kwilas, A.R., R.N. Donahue, K.Y. Tsang, and J.W. Hodge, Immune consequences of tyrosinekinase inhibitors that synergize with cancer immunotherapy. Cancer Cell Microenviron, 2015.
Kryukov GV, Wilson FH, Ruth JR, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016;351(6278):1214-1218. doi:10.1126/science.aad5214
Marjon K, Cameron MJ, Quang P, et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 2016;15(3):574-587. doi:10.1016/j.celrep.2016.03.043
Mavrakis KJ, McDonald ER 3rd, Schlabach MR, et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science. 2016;351(6278):1208-1213. doi:10.1126/science.aad5944
Han G, Yang G, Hao D, et al. 9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy. Nat Commun. 2021 Sep 23;12(1):5606. doi: 10.1038/s41467-021-25894-9.
Smith C.R., Aranda R, Bobinski T.P., Briere D.M., Burns A.C., et al. Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers. J Med Chem. 2022 Jan 18. doi: 10.1021/acs.jmedchem.1c01900. Online ahead of print.
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