Stomach Cancer: How Immunotherapy and Targeted Therapy are Changing Treatment

The approval of a targeted therapy and an immunotherapy drug for some patients with advanced stomach cancer reflects recent new approaches to this difficult-to-treat cancer that hasn’t had many therapeutic advances in recent years.

Stomach cancer, uncommon in the United States but a leading cause of cancer death globally, causes few definitive symptoms in early stages and is usually diagnosed too late for curative therapy. The main treatment for stomach cancer is surgery to remove the tumor, combined with chemotherapy, which can be given before or after surgery. Radiation therapy may also be used in combination with surgery or chemotherapy.

Investigators led by Dana-Farber's Adam Bass, MD, led to the identification of four subtypes of stomach cancers.

Unlike many other types of cancer, stomach cancer research has seen few developments leading to precision therapies that can home in on molecular weak points to halt or shrink tumors. One such therapy, approved in 2010, targets a protein, HER2, that is over-expressed on the surface of about 20 to 25 percent of stomach cancers. The drug trastuzumab (Herceptin) was approved for use with chemotherapy in patients with HER2-overexpressing metastatic cancer of the stomach or gastroesophageal junction – the area where the stomach and esophagus meet. Other drugs that target HER2, such as lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla), are now being studied in clinical trials.

Immunotherapy drugs, which help the patient’s immune system seek out and destroy tumor cells, have proven very effective for some patients with advanced melanoma, non-small cell lung cancer, kidney cancer, and other cancer types. In September 2017, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for people with certain advanced cancers of the stomach or the gastroesophageal junction.

The approval applies to patients with advanced cancers, called adenocarcinomas, that have come back or continued to grow after having at least two previous treatments. The cancer cells must also test positive for the PD-L1 protein, which allows some cells to escape attack by the immune system. The FDA also approved a new lab test to check these cancers for the PD-L1 protein and determine whether the patient is likely to benefit from cancer drugs known as immune checkpoint inhibitors.

Pembrolizumab has also been approved to treat any type of tumor that is so-called MSI-High, meaning its cells exhibit microsatellite instability. A small percentage of stomach cancers have this characteristic.

In an effort to diagnose stomach cancer earlier, researchers are looking at known risk factors, such as mutations that run in certain families that increase the risk of the disease, although these are rare.

The strongest known risk factor for stomach cancer is infection with the H. pylori bacterium, which is found in about 50 percent of the world’s population. H. pylori infection causes chronic inflammation and increases the risk of developing ulcers and stomach cancer. However, most people whose stomachs harbor the bug don’t develop cancer.

Studies are being conducted to see whether antibiotic treatment of people who are chronically infected by H pylori will help prevent stomach cancer. Some studies have found that treating this infection may prevent precancerous stomach abnormalities, but more research is needed.

Another research effort, which has led to the identification of four subtypes of stomach cancers, highlights the complexity of the disease, and may eventually lead to more precise treatments. Investigators led by Adam Bass, MD, reported that analysis of 295 samples of stomach cancers revealed four groups that had distinct features and types of molecular alterations.

Bass, who directs the Center for Esophageal and Gastric Cancer at Dana-Farber, says that grouping the cancers this way will help researchers enroll patients in clinical trials that test drugs aimed at targeting their specific stomach cancer subtype.

Precision Medicine and Targeted Therapy .

What Is Precision Medicine?

Precision medicine refers to the use of information about the genes, proteins, and other features of a person’s cancer to diagnose or treat their disease.

What Is Targeted Therapy?

Targeted therapy is the foundation of precision medicine. It is a type of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spread. As researchers learn more about the cell changes that drive cancer, they are better able to design promising therapies that target these changes or block their effects.

Types of Targeted Therapy

Most targeted therapies are either small-molecule drugs or monoclonal antibodies.

Small-molecule drugs are small enough to enter cells easily, so they are used for targets that are inside cells.

Monoclonal antibodies are drugs that are not able to enter cells easily. Instead, they attach to specific targets on the outer surface of cancer cells.

Who Receives Targeted Therapy

For some types of cancer, most patients with that cancer will have a target for a certain drug, so they can be treated with that drug. But, most of the time, your tumor will need to be tested to see if it contains targets for which we have drugs.

To have your tumor tested for targets, you may need to have a biopsy. A biopsy is a procedure in which your doctor removes a piece of the tumor for testing. There are some risks to having a biopsy. These risks vary depending on the size of the tumor and where it is located. Your doctor will explain the risks of having a biopsy for your type of tumor.

How Targeted Therapy Works Against Cancer

Most targeted therapies help treat cancer by interfering with specific proteins that help tumors grow and spread throughout the body. They treat cancer in many different ways. They can:

  • Help the immune system destroy cancer cells. One reason that cancer cells thrive is because they are able to hide from your immune system. Certain targeted therapies can mark cancer cells so it is easier for the immune system to find and destroy them. Other targeted therapies help boost your immune system to work better against cancer.
  • Stop cancer cells from growing. Healthy cells in your body usually divide to make new cells only when they receive strong signals to do so. These signals bind to proteins on the cell surface, telling the cells to divide. This process helps new cells form only as your body needs them. But, some cancer cells have changes in the proteins on their surface that tell them to divide whether or not signals are present. Some targeted therapies interfere with these proteins, preventing them from telling the cells to divide. This process helps slow cancer’s uncontrolled growth.
  • Stop signals that help form blood vessels. Tumors need to form new blood vessels to grow beyond a certain size. These new blood vessels form in response to signals from the tumor. Some targeted therapies are designed to interfere with these signals to prevent a blood supply from forming. Without a blood supply, tumors stay small. Or, if a tumor already has a blood supply, these treatments can cause blood vessels to die, which causes the tumor to shrink.
  • Deliver cell-killing substances to cancer cells. Some monoclonal antibodies are combined with toxins, chemotherapy drugs, and radiation. Once these monoclonal antibodies attach to targets on the surface of cancer cells, the cells take up the cell-killing substances, causing them to die. Cells that don’t have the target will not be harmed.
  • Cause cancer cell death. Healthy cells die in an orderly manner when they become damaged or are no longer needed. But, cancer cells have ways of avoiding this dying process. Some targeted therapies can cause cancer cells to go through this process of cell death.
  • Starve cancer of the hormones it needs to grow. Some breast and prostate cancers require certain hormones to grow. Hormone therapies are a type of targeted therapy that can work in two ways. Some hormone therapies prevent your body from making specific hormones. Others prevent the hormones from acting on your cells, including cancer cells.

Drawbacks of Targeted Therapy

Targeted therapies do have some drawbacks. These include:

  • Cancer cells can become resistant to them. For this reason, targeted therapies may work best when used with other targeted therapies or with other cancer treatments, such as chemotherapy and radiation.
  • Drugs for some targets are hard to develop. Reasons include the target’s structure, the target’s function in the cell, or both.

Targeted Therapy Can Cause Side Effects

Targeted therapy can cause side effects. The side effects you may have depend on the type of targeted therapy you receive and how your body reacts to the therapy.

The most common side effects of targeted therapy include diarrhea and liver problems. Other side effects might include problems with blood clotting and wound healing, high blood pressure, fatigue, mouth sores, nail changes, the loss of hair color, and skin problems. Skin problems might include rash or dry skin. Very rarely, a hole might form through the wall of the esophagus, stomach, small intestine, large bowel, rectum, or gallbladder.

There are medicines for many of these side effects. These medicines may prevent the side effects from happening or treat them once they occur.

Most side effects of targeted therapy go away after treatment ends.

Other Risks

Since your tumor may be tested to find targets for treatment, there may be risks to the privacy of your personal information. The privacy of all information found from these tests is protected by law. But, there is a slight risk that genetic or other information from your health records may be obtained by people outside of the medical team.

Having Targeted Therapy

How Targeted Therapies Are Given

Small-molecule drugs are pills or capsules that you can swallow.

Monoclonal antibodies are usually given through a needle in a blood vein.

Where You Go For Your Treatment

Where you go for treatment depends on which drugs you are getting and how they are given. You may take targeted therapy at home. Or, you may receive targeted therapy in a doctor’s office, clinic, or outpatient unit in a hospital. Outpatient means you do not spend the night in the hospital.

How Often You Will Receive Treatment

How often and how long you receive targeted therapy depends on:

  • Your type of cancer and how advanced it is
  • The type of targeted therapy
  • How your body reacts to treatment

You may have treatment every day, every week, or every month. Some targeted therapies are given in cycles. A cycle is a period of treatment followed by a period of rest. The rest period gives your body a chance to recover and build new healthy cells.

How Targeted Therapy May Affect You

Targeted therapy affects people in different ways. How you feel depends on how healthy you are before treatment, your type of cancer, how advanced it is, the kind of targeted therapy you are getting, and the dose. Doctors and nurses cannot know for certain how you will feel during treatment.

How to Tell Whether Targeted Therapy Is Working

You will see your doctor often. He or she will give you physical exams and ask you how you feel. You will have medical tests, such as blood tests, x-rays, and different types of scans.

MAP kinase signaling and inhibition in melanoma..

The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

Source: Oncozene


New options for second-line therapy of advanced renal cancer.


Several drugs targeting VEGF or mTOR pathways have been approved for treatment of advanced renal-cell carcinoma because of improvements noted in progression-free survival (PFS) in phase 3 trials.1 Validation of prognostic models showed that treatment with such drugs can lead to a median overall survival of around 43 months for patients in favourable risk categories and 23 months for patients in intermediate risk categories.2 With few exceptions, patients on first-line therapy progress and proceed to need one or more subsequent lines of targeted therapy. In a population-based study,3 patients in a favourable risk group had progression on first-line VEGF-targeted therapy after a median of 16·6 months (compared with 15 months for patients in an intermediate risk group) and progression after 6·2 months on second-line targeted therapy (5·5 months for intermediate risk). Two phase 3 trials45 assessed outcomes after failure of a previous VEGF-targeted therapy to establish evidence for the mTOR-inhibitor everolimus and the selective inhibitor of VEGF receptors 1—3, axitinib. The AXIS trial5 is the only study that directly compared two active compounds (axitinib vs sorafenib) after failure of an approved first-line regimen. In AXIS, more than a third of patients had received cytokines and over half had received sunitinib as first-line therapy. Axitinib led to an improvement in median PFS compared with sorafenib in the intention-to-treat analysis. However, the difference in PFS for patients after sunitinib treatment based on investigator and independent review committee assessments was only slight. Data for overall survival, a secondary endpoint, were immature before the first report was published in 2011. Because guidelines and clinical practice favour targeted therapy in preference to cytokines as first-line treatment,1 axitinib is regarded as a treatment option for second-line therapy of advanced renal-cell carcinoma.5

In The Lancet Oncology, Robert Motzer and colleagues6 now report mature overall survival data for the AXIS trial. Such an analysis is important because crossover between the two study arms was not allowed. No significant differences in overall survival were noted between patients in both treatment arms who received the same first-line regimen (median overall survival 20·1 months [95% CI 16·7—23·4] with axitinib vs 19·2 months [17·5—22·3] with sorafenib; hazard ratio 0·969, 95% CI 0·800—1·174, p=0·3744). More than half the patients in each arm continued with a third-line treatment after progression on study drug and treatment after progression was allowed. This design confounded overall survival results and raises questions as to whether PFS is meaningful in this setting.7 Third-line therapy partly explains the long time interval noted between progression on second-line treatment and overall survival. However, inclusion of patients with a less aggressive tumour biology might have contributed to this outcome. Only a third of patients in the AXIS trial were Memorial Sloan Kettering Cancer Center (MSKCC) poor risk at entry,5 suggesting that individuals with rapid deterioration of performance or accelerated progression during first-line therapy are less likely to enter trials than are patients with more favourable risk profiles.

For patients previously treated with sunitinib in Motzer and colleagues’ study,6 median time on first-line therapy was about 10 months, with a median overall survival for all risk groups of 15·2 months (95% CI 12·8—18·3) for axitinib and 16·5 months (13·7—19·2) for sorafenib. Patients who received cytokines had first-line therapy for about 6 months and a median overall survival of 29·4 months (24·5—not assessable) for axitinib and 27·8 months (23·1—34·5) for sorafenib. After correction for the different length of first-line therapies, overall survival seemed to be increased by about 7—9 months in patients who had cytokines before VEGF-targeted therapy. Resistance to previous VEGF-targeted therapy, which might not be apparent in patients previously untreated with such an approach, cannot fully explain this difference. Motzer and colleagues noted a putative association of overall survival with length of previous sunitinib treatment for both axitinib and sorafenib, although there was substantial overlap in the 95% CIs.6 A retrospective Database Consortium analysis of 464 patients who had received two lines of VEGF-targeted therapies reported no correlation between first-line PFS and second-line PFS.8 Rather, a significant difference in multivariate analysis of baseline prognostic factors in favour of cytokine versus sunitinib pretreatment (HR 0·503, 95% CI 0·395—0·641; p<0·0001) suggested that patients with less advanced disease were most likely to start treatment with cytokines.6 However, information about the distribution of prognostic factors between patients who were pretreated with cytokines and sunitinib, which could have important implications for treatment sequences, is not provided in Motzer and colleagues’ study.

Data from trials and population-based analyses suggest that a ceiling has almost been reached in terms of outcome with present targeted therapies and prognosis that relies on models based on clinical factors.2 The mature AXIS data add axitinib to the choices for second-line treatment with similar outcome and different toxicity profiles.4—6 Despite prognostic factors assessed in the updated analysis and a correlation of development of hypertension during axitinib and sorafenib treatment with overall survival, the choice for a second-line drug or even treatment beyond progression at failure of first-line treatment remains an educated guess. The outcome of this study proves once again that renal-cell carcinoma is a heterogenous cancer9 that needs further research into predictive biomarkers to tailor treatment choices.

Source: Lancet


Study reports first success of targeted therapy in most common genetic subtype of non-small cell lung cancer.

A novel compound has become the first targeted therapy to benefit patients with the most common genetic subtype of lung cancer, an international clinical trial led by scientists at Dana-Farber Cancer Institute and other institutions will report at the annual meeting of the American Society of Clinical Oncology (ASCO) June 1-5 in Chicago.

Pasi Jänne, MD, PhD, scientific co-director of Dana-Farber’s Belfer Institute for Applied Cancer Science, will present the findings from the phase II study (abstract 7503) on Monday, June 4, 3 p.m. CT, E Hall D2, McCormick Place.

The study involved 87 non-small cell lung cancer (NSCLC) patients whose tumors carry a mutation in the gene KRAS. Such tumors account for about 20 percent of NSCLC cases, but no targeted therapy has proved effective against them in previous clinical research. The drug under investigation, selumetinib, doesn’t attack KRAS directly, but interferes with one of its molecular henchmen, a protein called MEK.

Participants in the study all had advanced stages of the disease. They received the standard chemotherapy agent docetaxel in combination with either selumetinib or a placebo.

By many measures – the rate and duration of response to treatment, change in tumor size, and proportion of patients alive and showing no signs of advancing disease – the group receiving selumetinib did significantly better than the other group. Most clinically significant were the improved rate of response to treatment (37 percent compared to 0 percent in the placebo arm) and prolonged progression-free survival (5.3 months compared to 2.1 months in the placebo arm). Although patients in the selumetinib group survived longer, on average, than those in the placebo group – 9.4 months compared to 5.2 months – the improvement was not considered statistically significant.

“This clinical trial demonstrates that a combination of chemotherapy and selumetinib is significantly better than chemotherapy alone for this group of patients – better in terms of tumor response to therapy and in terms of survival times prior to advance of the disease,” says Jänne. “It suggests that for the first time we may have an effective treatment for KRAS-mutant lung cancer, which is the largest single subtype of the disease. These impressive clinical findings not only have implications for the treatment of lung cancer but all cancers that harbor KRAS mutations, including pancreatic and colorectal cancer.”

Some side effects, such as neutropenia (a white blood cell deficiency), loss of strength, acne, and respiratory problems were more common in the selumetinib group than the other, but the rate of patients dropping out of the study because of severe side effects was similar for both groups.

The study involved a collaboration among researchers and clinicians at 67 medical centers and clinics in 12 countries. Contributors include investigators at Dana-Farber; Massachusetts General Hospital; Instituto Brasileiro de Cancerologia Toracica, Sao Paulo, Brazil; Service Pneumologie Oncologie Thoracique, Clermont Ferrand, France; University Hospital Gasthuisberg, Leuven, Belgium; PUCRS School of Medicine, Porto Alegre, Brazil; Hospital de Caridade de Ijui, Ijui, Brazil; AstraZeneca; and the University of Perugia, Perugia, Italy.

The study was sponsored by AstraZeneca.

At Dana-Farber, patients receive lung cancer treatment through the Lowe Center for Thoracic Oncology.

Source: Dana Faber cancer Institute.


cancer chemotherapy resistance

Primary or acquired drug resistance remains a fundamental cause of therapeutic failure in cancer therapy. Post-hoc analyses of clinical trials have revealed the importance of selecting patients with the appropriate molecular phenotype for maximal therapeutic benefit, as well as the requirement to avoid exposure and potential harm for those who have drug resistant disease, particularly with respect to targeted agents. Unravelling drug resistance mechanisms not only facilitates rational treatment strategies to overcome existing limitations in therapeutic efficacy, but will enhance biomarker discovery and the development of companion diagnostics. Advances in genomics coupled with state-of-the-art biomarker platforms such as multi-parametric functional imaging and molecular characterisation of circulating tumour cells are expanding the scope of clinical trials – providing unprecedented opportunities for translational objectives that inform on both treatment response and disease biology. In this review, we propose a shift towards innovative trial designs, which are prospectively set up to answer key biological hypotheses in parallel with the RNA interference elucidation of drug resistance pathways in monotherapy pre-operative or ‘window of opportunity’ early phase trials. Systematic collection of paired clinical samples before and after treatment amenable to genomics analysis in such studies is mandated. With concurrent functional RNA interference analysis of drug response pathways, the identification of robust predictive biomarkers of response and clinically relevant resistance mechanisms may become feasible. This represents a rational approach to accelerate biomarker discovery, maximising the potential for therapeutic benefit and minimising the health economic cost of ineffective therapy.

Inflaming resistance to Tarceva

A team at Cold Spring Harbor Laboratory has found that in cancer, inflammation-driven IL-6 signaling can cause resistance to drugs that inhibit epidermal growth factor receptor, such as Tarceva erlotinib and Iressa gefitinib.1 The data suggest that blocking IL-6 could help treat drug-resistant cancers, a hypothesis Alder Biopharmaceuticals Inc. may put to the test in a Phase IIa trial of its anti-IL-6 antibody, ALD518.

About 80% of patients who respond to small molecule inhibitors of epidermal growth factor receptor (EGFR) carry oncogenic mutations in the kinase domain of the receptor that render them sensitive to EGFR inhibition.2 However, all patients will eventually develop resistance to these drugs.

Half of resistant cases stem from secondary mutations within EGFR or amplification of c-Met proto-oncogene (MET; HGFR). In the other half of cases, the mechanisms underlying resistance are unknown.

Thus, a team led by Raffaella Sordella, assistant professor at Cold Spring Harbor Laboratory, sought to identify new mechanisms of drug resistance. The researchers started by selecting EGFR mutant cell lines that were resistant to Tarceva but lacked any of the known mutations that confer resistance.

“We noticed these erlotinib-resistant cells had a dramatically different morphology than erlotinib-sensitive cells,” Sordella told SciBX. “We performed gene expression profiling to understand what was different about them.”

Her team found that transforming growth factor-β (TGFB; TGFβ) was induced in resistant cells, explaining their difference in morphology. Moreover, IL-6 secretion from these cells was induced more than 10-fold, and the increase required TGFβ.

Adding IL-6 to erlotinib-sensitive cells increased their resistance to the drug compared with that of cells not given IL-6.

Sordella’s team also examined non–small cell lung cancer (NSCLC) samples isolated from Tarceva-naïve patients and found that a subpopulation of cells had high levels of TGFβ and IL-6. That finding suggests some tumor cells may be intrinsically resistant to Tarceva.

Tarceva is marketed by Astellas Pharma Inc. and Roche‘s Genentech Inc. unit, whereas Iressa is marketed by AstraZeneca plc.

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No escape

“These experiments demonstrate that high levels of IL-6 driven by TGFβ can release cancer cells from their dependency on EGFR signaling,” said Sordella.

Alder may put that mechanism to the test. “We are strongly considering running a Phase IIa trial examining the effect of combination therapy using ALD518 and Tarceva,” Mark Litton, CBO and cofounder, told SciBX. “It is very timely that this paper has come out suggesting that this could be beneficial.”

“By only targeting EGFR, you select for the survival of cells that express high levels of IL-6 independent of EGFR signaling,” noted Jeffrey Smith, CMO and cofounder of Alder. “If you block both IL-6 and EGFR, you stop this escape mechanism.”

Smith said the Phase IIa trial is in the planning stages and will compare the efficacy of Tarceva alone with that of ALD518 plus Tarceva. In addition to the standard endpoints such as response rate, progression-free survival (PFS) and overall survival (OS), they plan to do molecular phenotyping to look at the response in more detail to aid in the design of possible Phase IIb/III studies.

The biotech already has tested ALD518 as a stand-alone therapy. In June, the company announced preliminary data from a Phase IIa trial of the antibody to treat cachexia and anemia in late-stage NSCLC patients. Patients receiving ALD518 had higher hemoglobin levels and less weight loss than patients given placebo.

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Other options

The results from the Cold Spring Harbor group, which were published in the Proceedings of the National Academy of Sciences, build on previous studies that illustrated IL-6’s role in EGFR mutant lung cancers.

In 2007, a group led by Jacqueline Bromberg, associate professor of medicine at Memorial Sloan-Kettering Cancer Center, showed that EGFR mutant NSCLC samples expressed high levels of IL-6. Inhibiting IL-6 or its downstream signaling partners, including Janus kinase (JAK), stopped cancer growth in xenograft mice carrying NSCLC cells3 (see Figure 1, “Targeting Tarceva resistance”).

Figure 1: Targeting Tarceva resistance.

Figure 1 : Targeting Tarceva resistance.Yao et al. suggest that blocking IL-6 signaling could reduce resistance to epidermal growth factor receptor (EGFR) inhibitors like Tarceva erlotinib. In non–small cell lung cancer (NSCLC), mutations in the kinase domain of EGFR [a] lead to increased production and secretion of IL-6. IL-6 signals through gp130, Janus kinase-1 (JAK-1) and JAK-2 to increase phosphorylation (P) of signal transducer and activator of transcription 3 (STAT3), a prosurvival transcription factor [b]. Thus, by blocking EGFR, a tumor should be rendered unable to progress. But in Tarceva-resistant tumors, transforming growth factor-β (TGFB; TGFβ) upregulates IL-6 independent of EGFR signaling [c].

Full figure and legend 68K

Bromberg told SciBX that the new PNAS paper “advances the field by demonstrating a link between TGFβ and IL-6 signaling. It suggests that a combined approach blocking both EGFR and JAK/STAT signaling could be beneficial for cancer treatment.”

Blocking this pathway could be broadly beneficial in EGFR mutant cancer. In addition to its role in NSCLC, a recent study suggests the JAK and signal transducer and activator of transcription (STAT) pathway may be a therapeutic target in EGFR mutant glioblastoma multiforme4 (see Box 1, “Targeting IL-6 in glioblastoma”).

Incyte Corp.‘s INCB18424, the most advanced JAK-1 and JAK-2 inhibitor, is in Phase III testing to treat myelofibrosis. Incyte declined to comment for this article. At least six other companies have compounds in development to block IL-6 and JAK signaling in cancer and autoimmune disease.

In addition to specifically targeting the IL-6 pathway, Sordella suggested that generally targeting inflammation, for example with a cyclooxygenase-2 (COX-2) inhibitor, could help treat Tarceva-resistant cancers.

“Inflammation involves the recruitment of immune cells, which can ultimately lead to increased levels of IL-6,” she said. “It is important to understand the influence of the tumor microenvironment on drug sensitivity.”

For example, her team reported in the PNAS paper that lipopolysaccharide (LPS), a general stimulator of inflammation, induced IL-6 expression in mice and reduced NSCLC sensitivity to Tarceva compared with no treatment.

Kevin Struhl, professor of biological chemistry and molecular pharmacology at Harvard Medical School, also argued for a broad attack against inflammation. “My view is that the inflammatory pathway is acting as a general stress response in many cell types,” he told SciBX.

Struhl’s lab has shown in cell culture studies that IL-6 can trigger a positive feedback loop that maintains cancer cell survival even in the absence of an initial oncogenic signal. In a paper published last month in Molecular Cell, members of his lab identified microRNA-21 (miR-21) as a key component of that positive feedback loop.5

miR-21 is upregulated in EGFR mutant NSCLC, and combined inhibition of miR-21 and EGFR triggered increased apoptosis in an NSCLC cell line.6

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Next steps

Regardless of whether inflammation is broadly dampened or specifically decreased via blocking IL-6, both Sordella and Bromberg said the key question is whether lower levels of inflammation could help treat EGFR-driven NSCLC in humans.

Bromberg is studying the effect of JAK inhibitors in mice with NSCLC. “So far our studies have shown blocking IL-6 signaling can stop tumor progression but does not cause tumor regression,” she said. “We still don’t know if targeting this pathway will be effective in treating disease.”

Sordella plans to continue studying the therapeutic effects of combination therapy using Tarceva in conjunction with IL-6 antibodies and JAK inhibitors in mouse models of NSCLC.

A patent application based in part on the work described in the paper and directed to use of IL-6 inhibitors in combination drug therapy for treatment of drug-resistant EGFR mutant NSCLC has been filed by Cold Spring Harbor Laboratory.