NEW YORK (GenomeWeb) – Researchers from the Worldwide Innovative Networking (WIN) Consortium recently modeled a way to map the critical molecular aberrations driving a lung cancer patient’s tumor and use it to personalize treatment with a three-drug cocktail.
Led by Razelle Kurzrock of the Moores Cancer Center at the University of California, San Diego, the researchers developed a so-called simplified interventional points mapping system (SIMS) that they used to sift through the complex web of molecular markers implicated in driving a tumor and prioritize the most “disturbed” druggable targets that can be used to personalized patients’ treatment with a three-drug strategy.
Kurzrock and colleagues described the method they used to develop SIMS in the open access peer reviewed journal Oncotarget earlier this month.
Vladimir Lazar, a lead study author from the Gustave-Roussy Cancer Center, highlighted that in developing SIMS his group integrated the latest knowledge about the molecular factors involved in cancer and tried to distill from a dizzyingly complex picture an algorithm that one day physicians could use to customize combination treatments for patients. “What is new here is the results integrate in a very simple manner, by scoring one to 10, thousands of ‘omics measurements,” Lazar, chief operating officer of the WIN Consortium, told GenomeWeb.
In the near term, the consortium hopes that with further validation SIMS can be used to design cancer trials investigating personalized targeted drug combinations that improve survival and outcomes for metastatic non-small cell lung cancer patients. According to the American Cancer Society, around 30 percent of patients diagnosed with stage II NSCLC, and between 5 percent and 14 percent of those with stage III disease, live for five years. Kurzrock and colleagues point out in their paper that after advanced NSCLC patients have failed first line therapy, median survival is around seven months.
Lazar noted that SIMS needs to be validated in a prospective clinical trial. To do that, the consortium has brought together stakeholders from industry and academia to launch the Survival Prolongation by Rationale Innovative Genomics (SPRING) trial. Additionally, the WIN Consortium recently announced that Waun Ki Hong will oversee its research efforts around NSCLC. Hong led the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, the first prospective, adaptively randomized study in NSCLC that employed “real-time” biopsies to profile patients’ tumors.
Using SIMS, the WIN Consortium is particularly eager to test out the triple-therapy approach – a strategy that has been successful in the treatment of AIDS and tuberculosis – in advanced NSCLC. By using SIMS to craft a precision treatment plan, researchers are hoping to identify triplet therapy combinations that NSCLC patients have the best chance of responding to. “Everyone agrees with the principle that the future might be in combinations of targeted therapies, but the main problem is how to select them and match the right patient to the right combination,” Lazar said. “The purpose of this paper is to lay out the scientific rationale as to how to select [treatment] combinations.”
In developing SIMS, researchers first identified so-called interventional points – 24 markers in 183 genes corresponding to biological activities that can be acted on by a drug. In the paper, study authors provided the example of the HER group of receptors and ligands as an interventional point that can be targeted by pan-HER targeted drugs.
Researchers then prioritized the interventional points based on how “disturbed” the genes are in terms of mutations, messenger RNA and microRNA expression levels, and copy number variations in tumor versus normal cells. “The more disturbed the genes of an intervention point, the higher the probability that therapeutics targeted at that point will impact the viability of tumor cells, and hence benefit the patient,” Kurzrock and colleagues reasoned in the paper.
Because mutations are known to drive cancer, they have the most weight in the algorithm. Then, gene expression is compared between tumor and normal samples. “The differential expression takes into account messenger RNA,” Lazar said, pointing out however that the “correlation between messenger RNA and proteins are not perfect.” To adjust for this, the algorithm also factors in the expression of the top five microRNAs that target the messenger RNA at an interventional point, and if there is discordance, the score is penalized. The impact of microRNAs is “dramatic” for some interventional points, but not others, Lazar noted.
Finally, the algorithm also factors in copy number variations and their impact on messenger RNA expression. “It happened in this set of genes, the impact of CNVs was quite low,” Lazar said. “The major players were the mutations, the messenger RNA, and the microRNA.”
Kurzrock and colleagues retrospectively generated these scores for interventional points identified in 121 patients who had their tumors surgically removed at a French institute between 2002 and 2006. While the method identified different high-scoring interventional points among these individuals, the patients shared several key commonly activated nodes. Kurzrock’s group further observed that, based on the scores, some patients could perhaps benefit from two or more triplet drug combos.
Interventional points that were commonly activated in 121 patients included CDK4/6, Ras/Raf, anti-apoptosis, Her, Notch and Polokinase-Aurora-Kinase. Immune-related interventional points, such as PD-L1 and CTLA4, showed up for more than half of the patients.
Kurzrock and colleagues homed in on six drug combinations involving anti-PD-L1 immunotherapy that the SIMS scores suggested might benefit at least half the NSCLC patients. For example, 28 percent of NSCLC patients had activation of RAS/RAF, mTOR/PI3K, and PDL1. For 19 percent of patients, the score prioritized PD-L1, mTOR/PI3K, and DNA repair mechanisms.
The commonly perturbed interventional nodes had targeted drugs (either approved or in clinical studies) associated with them. However, researchers noted that in the study there weren’t that many patients with EGFR mutations or ALK rearrangements, and so drug combinations targeting these markers occurred infrequently.
In advanced lung cancer, the standard of care is to combine chemotherapy with a targeted agent. Among patients who have EGFR or ALK mutations, personalized therapy options have improved response rates and extended progression-free survival. But “the problem with [these] monotherapies is secondary resistance,” Lazar noted.
This is why the WIN Consortium wants to test out the efficacy of triplet therapeutic strategies when they are given to patients based on the most perturbed molecular characteristics of their tumor. “Having a clear insight to what is wrong in the biology for the tumor as compared to the normal status, this is very useful information at different levels – at the level of better understanding the use of monotherapies but especially to provide the landscape for providing combined therapies,” Lazar said.
Triplet therapies have successfully improved long-term outcomes for patients with HIV or bacterial infections. Lazar noted that in AIDS, only the combination of three agents was able to control the viral load and reduce it to the status of a chronic disease. From this experience, Kurzrock’s group has a hypothesis that combining three drugs with different modes of action (targeting different interventional nodes) might just stave off resistance and prolong patient survival in NSCLC patients, too.
The complexity of cancer necessitates a multitude of three-drug combinations, in Lazar’s view. “You’ll never have one combination that’s good for all patients,” he said. “You’ll have to have multiple combinations that are preselected on a rational basis.”
But one of the challenges of giving cancer patients three drugs has been the risk that they’ll experience toxicities they can’t tolerate. Importantly, the SIMS algorithm pinpointed immune-related interventional points in more than half of the NSCLC patients, which would make immunotherapy part of their triplet combination. This is key, given the potential of immunomodulators to mitigate toxicities.
Also worth noting is that in this study, researchers collected molecular measurements on tumor versus normal samples. This is important because it means that the algorithm could be used in all solid tumors, but in order to do so, “you need to generate this knowledge,” Lazar said. He noted that worldwide most cancer research is only focused on analyzing the tumor.
A research team led by Victor Velculescu of the Sidney Kimmel Comprehensive Cancer Center recently published data showing that sequencing only the tumor, and not also the matched normal tissue, resulted in the identification of false-positive alterations, which would be thought of as actionable in terms of directing therapy based on tumor-only analysis.
“This paper makes me very happy,” Lazar said. “It’s indirect confirmation that … analyzing tumor versus normal [samples] will be more and more important.” The WIN Consortium is further studying this approach in the WINTHER trial, involving MD Anderson Cancer Center in the US, Institut Gustave Roussy in France, Vall d’Hebron Institute of Oncology in Spain, and the Chaim Sheba Medical Center in Israel.
Meanwhile, it will be some time before SIMS is integrated into the clinic. Forthcoming validation studies such as the SPRING trial will ultimately determine whether the algorithm becomes part of oncologists’ tool box. The WIN Consortium said it will discuss the latest study and provide further details on its overarching lung cancer clinical trials plan at the WIN 2015 Symposium in Paris in June.