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Exceptional Responders Cancer Study Points to Possible Treatment Targets

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NEW YORK – A team led by researchers at the National Cancer Institute has analyzed advanced cancer patients known as exceptional responders to therapy — those who survive significantly longer than individuals with clinically comparable tumors — and found plausible mechanisms for some related to DNA damage response, intracellular signaling, immune engagement, and genetic mutations.

For their study, published in Cancer Cell on Thursday, the researchers analyzed tumor biopsies from an unbiased cohort of 111 exceptional responders and detected mechanisms for their response, which fell into four broad categories, in about 23 percent. These individuals are defined as patients where a complete or partial response was expected in less than 10 percent of similarly treated patients, or whose duration of response lasted at least three times the published median.

The analyses revealed synthetic lethal relationships that could be exploited therapeutically, and rare genetic lesions that favor therapeutic success, while also providing a basis for testable hypotheses on oncogenic mechanisms that could influence response to therapy, the researchers noted.

Because exceptional responses in cancer are rare, the underlying causative genetic mechanisms would also be expected to be rare, the researchers wrote. Genetic events conferring therapeutic responsiveness fall into two broad classes: oncogene addiction and synthetic lethality. In the first, a genetic change in a tumor cell renders it exceptionally dependent on the encoded protein and sensitive to therapies targeting the protein or downstream pathways. Synthetic lethality is the concept of cell death through a combination of deficiencies in the expression of two or more genes.

Mammalian cells have redundant regulatory circuits that regulate phenotypes like proliferation and survival. If a tumor has a mutation that inactivates one of two parallel signaling pathways that control cell survival, a drug targeting the second pathway could be effective against that tumor. But because there can be more than two redundant pathways controlling an essential cellular function, a therapeutic response can only occur in tumors that have inactivated more than one of those parallel pathways. And since tumors with such a precise combination of genetic aberrations are uncommon, such a response can be considered exceptional, the researchers said.

Previous studies of exceptional responders have largely focused on analyses of somatic mutations. For this study, the researchers analyzed mutations, copy number changes, aberrant methylation, outlier gene expression, and the cellular makeup of the tumor microenvironment.

This integrative approach allowed them to propose a mechanistic explanation for the exceptional response in 26 (23.4 percent) of the 111 cases, including eight cancers of the brain, six GI tract cancers, four breast cancers, two cholangiocarcinomas, two lung cancer cases, a pancreas cancer case, an endometrium cancer case, an ovarian cancer case, and a bladder cancer case. DNA-damaging agents were used to treat 17 of these 26 patients, either alone or together with targeted agents. Targeted therapies were used to treat 14 patients.

The analyses also found that 16 of the cases involved mechanisms of immunologic engagement, 15 involved DNA damage response, nine involved intracellular signaling pathways, and another nine involved prognostic mutations. Many cases involved two or more of these mechanisms.

In some of the cases, the explanation for the exceptional response "wasn't so complicated," said NCI researchers and senior author Louis Staudt. "Sometimes there was one genetic lesion, for example, in the DNA repair polymerase that is known to create a hypermutated genome and that has been associated with favorable outcome for therapy in general," he said. "But in many cases, there was more than one thing happening. And that makes sense because normal cells have a number of failsafe mechanisms that allow that cell to avoid various pitfalls and damage to the genome in proper cell division and all sorts of checkpoints."

Tumors inactivate a cell's checkpoints to create a malignant state, he explained. In order for therapeutics to be effective, they need to interfere with some of the control pathways in the tumor cell, and the more control mechanisms that are taken away, the more exceptionally effective the drug will be.

In one case involving DNA damage response, for example, the researchers found that a patient with metastatic colon adenocarcinoma achieved an ongoing, nearly complete response lasting 45 months at last follow-up after receiving temozolomide (Merck's Temodar) in combination with Tracon Pharmaceuticals' investigational drug TRC102 in a phase 1 clinical trial. TRC102 is a clinical-stage small molecule inhibitor of the DNA base excision repair pathway. In this tumor, MGMT expression was silenced by promoter methylation, alongside a series of other rare events. The researchers hypothesized that the combination of temozolomide and TRC102 was effective in this patient because all necessary DNA repair pathways were compromised genetically, epigenetically, or pharmacologically.

Importantly, the clinical trial testing temozolomide plus TRC102 was expanded to include an additional cohort of 16 patients with colon adenocarcinoma, among whom there was one more partial response. MGMT expression was measured by immunohistochemistry in biopsies from 11 patients in this expansion cohort, and the tumor associated with the partial response did not express MGMT, whereas 10 tumors that did not respond to the combination therapy did express MGMT. Those findings are in keeping with the mechanism observed for the exceptional responder patient, and could point a way forward for an effective therapy in patients whose tumors lack MGMT expression, the researchers said.

This particular example proves the value of this kind of analysis as a possible avenue for finding new combinations of therapies, Staudt noted.

"You have that evidence that these two pathways are important. It came from the analysis of that first patient with exceptional response," he said. "Now, in this particular case, we had a drug that targeted one of those pathways and showed that it worked. And to extend that a little bit further, there was even a third pathway that seemed to be important. And there are drugs that are being developed for that third pathway. So, could one even conceive of a cocktail of drugs that could target several of these DNA repair pathways? We'd have to see whether they could be combined in a safe way in humans, but that's sort of where the data takes us."

The investigators made similar observations for the other three mechanisms. In the case of intracellular signaling pathways, for example, a patient with a gastrointestinal stromal tumor had a deletion of KIT exon 11, resulting in a constitutively active KIT isoform. The patient relapsed after an initial response to imatinib (Novartis' Gleevec), which targets KIT, but then achieved a complete response to sunitinib (Pfizer's Sutent). Gene expression profiling revealed high expression of KIT as well as genes encoding several tyrosine kinases that are targeted by sunitinib, such as KDR, FLT1, and FLT3, potentially accounting for the exceptional complete response, the researchers said.

Notably, previous studies had associated high expression of these targets with response to sunitinib, and a randomized phase 3 trial of the drug in 2011 showed prolonged progression-free and overall survival in patients with pancreatic neuroendocrine tumors, which are characterized by high expression of FLT1 and/or KDR in the absence of recurrent mutations in either gene.

Interestingly, the investigators noted that 16 of the 26 cases for which they observed possible exceptional response mechanisms harbored molecular changes that suggested classification into two or more categories. One patient with stage IVb endometrial cancer achieved a complete response with paclitaxel, carboplatin, and temsirolimus and was alive without evidence of disease nearly six years after diagnosis. Exome sequencing showed that inactivating mutations targeting three proteins involved in DNA repair could have sensitized the tumor to carboplatin therapy, the researchers said. In addition, an activating PIK3CA mutation and an inactivating PTEN mutation could have fostered addiction to PI3 kinase/mTOR signaling and sensitivity to the mTORC1 inhibitor temsirolimus.

Further, tumor sequencing revealed microsatellite instability due to methylation and silencing of MLH1. Endometrial cancers with such instability are associated with a relatively favorable prognosis and abundant microenvironmental immune cells, as was observed in this tumor, the researchers said. This patient's tumor exhibited features of all four exceptional response categories, they added, and the outcome could have been underpinned by one or all of them working together.

Importantly, though this was a scientific study, there may be some lessons for how cancer patients are tested in the clinic. Next-generation sequencing has been used to great effect in clinical settings to identify mutations, Staudt said, but this study also showed the value of copy number changes, translocations, gene expression changes, and methylation.

"You cannot conclude that the routine diagnosis of cancer needs to include all those," he said. "What we have to do is learn, in particular cancer types, what the molecular abnormalities are that are particularly relevant, and then make sure that they are included. And I would say that in terms of routine cancer screening, there's a lot of evidence now that mutations are an important first step. So, I personally would be thrilled if all patients with cancer in the United States would get sequencing of a goodly number of their cancer genes."

Co-senior author and NCI researcher Percy Ivy also emphasized a need for better knowledge of gene expression paired with data on mutations. Staudt agreed, noting his area of expertise — lymphoma research. Gene expression research on lymphoma led to the discovery of two subtypes of Diffuse Large B-Cell Lymphoma, and a combination of gene expression and mutation data is helping researchers hone in on why some patients respond better to treatment than others.

"These are stepwise approaches in which we take a systematic look at what is going on at a snapshot in time for an individual patient, and get those patients to help inform us," Ivy said. "By the same token, we inform them of what might be feasible therapy for them that could be effective. So, I hope that as we gain knowledge from our patients, we will better understand the ways to treat them."

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