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Proceedings of the NYAS

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Harnessing Cell Signaling to Treat Cancer

The 2015 Ross Prize in Molecular Medicine

Speakers: José Baselga (Memorial Sloan-Kettering Cancer Center) and Lewis C. Cantley (Weill Cornell Medical College)Presented by the Feinstein Institute for Medical ResearchMolecular Medicine, and the New York Academy of Sciences

Reported by Hema Bashyam | Posted September 10, 2015

http://www.nyas.org/Publications/EBriefings/Detail.aspx?cid=9f87d38e-7295-4205-a46e-6d5839c8a471

The Ross Prize in Molecular Medicine was established in conjunction with the Feinstein Institute for Medical Research and Molecular Medicine.  The Prize recognizes biomedical scientists whose discoveries have changed the way medicine is practiced.  It is awarded to scientists who have made a significant impact in the understanding of human disease pathogenesis and/or treatment and who hold significant promise for making even greater contributions to the general field of molecular medicine.

The 2015 Ross Prize in Molecular Medicine was awarded to Dr. Lewis C. Cantley for his critical discoveries regarding signaling pathways in cancer cells. Dr. Cantley discovered the phosphoinositide 3-kinases (PI3K), which are critical for cell growth, proliferation, and survival. Following this discovery, he demonstrated that activity-enhancing mutations in PI3K were present in several types of human cancer, and he continued to investigate small molecule inhibitors of PI3K that are now approved for use in the treatment of cancer.

PI3K.Akt signaling pathway

PI3K.Akt signaling pathway

PI3K signaling pathway inhibitors in solid tumors and hematological malignancies

PI3K signaling pathway inhibitors in solid tumors and hematological malignancies

On June 8, 2015, the Feinstein Institute for Medical Research and its journal Molecular Medicine presented the 2015 Ross Prize at the New York Academy of Sciences. The Feinstein Institute’s focus is on advancing science to prevent disease and cure patients. Established in 2013, the prize has gone to scientists who have made seminal scientific observations and translated their findings into clinical applications. The symposium, titled Harnessing Cell Signaling Pathways to Treat Cancer, honored Lewis C. Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College and New York-Presbyterian Hospital.

Cantley’s work on cellular responses to growth factors and hormones and his discovery of the enzyme phosphoinositide 3-kinase (PI3K), its signaling pathway, and the PI3K activity-enhancing mutations in several cancers furthered the current understanding of cell growth, malignant transformation, and the relationship between metabolism and cancer. The PI3K enzyme, which produces a cancer-driving lipid, is the target of several inhibitor molecules now in clinical trials for different types of cancer. Idelalisib, the first PI3K inhibitor to win FDA approval, has been a second-line treatment for chronic lymphocytic leukemia since mid-2014.

Harnessing Cell Signaling to Treat Cancer: The 2015 Ross Prize in Molecular MedicineAcademy eBriefings. 2015. Available at: www.nyas.org/RossPrize2015-eB

Advances in Immunomodulation

The 2014 Ross Prize in Molecular Medicine

Speakers: James P. Allison (University of Texas MD Anderson Cancer Center), Charles A. Dinarello (University of Colorado–Denver), and John J. O’Shea (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH)

Presented by the Feinstein Institute for Medical Research, Molecular Medicine, and the New York Academy of Sciences

Reported by Hema Bashyam | Posted August 12, 2014

On June 9, 2014, the Feinstein Institute for Medical Research and Molecular Medicine presented the 2014 Ross Prize in Molecular Medicine at New York Academy of Sciences. The symposium, titled Advances in Immunomodulation, honored this year’s awardee, John J. O’Shea, scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH). The award ceremony was followed by presentations by O’Shea and other immunologists, who described discoveries that have enabled therapeutic targeting of cytokine signaling molecules in autoimmune and inflammatory diseases and of immune checkpoint modulators such as CTLA4 in cancer.

https://youtu.be/3dtKDonbraA

The 2014 Ross Prize in Molecular Medicine was awarded to Dr. John J. O’Shea for his discoveries in immunology and cytokine biology.

Cancer Cell Metabolism

Unique Features Inform New Therapeutic Opportunities

Organizers: Lydia Finley (Memorial Sloan-Kettering Cancer Center), Steven S. Gross (Weill Cornell Medical College), Costas A. Lyssiotis (Weill Cornell Medical College), and Sonya Dougal (The New York Academy of Sciences)
Keynote Speaker: Craig B. Thompson (Memorial Sloan-Kettering Cancer Center)Presented by Hot Topics in Life Sciences

Reported by Paul Riccio | Posted August 14, 2015

Cancer cells become lethal when they form large tumors, metastasize, and colonize diverse tissue types. These functions depend on different metabolic pathways from those active in non-transformed cells. Rapidly growing and proliferating cells require constant biosynthesis, in addition to energy in the form of ATP that all cells need for normal functions. The glucose and glutamine that are exclusively catabolized to water and carbon dioxide in quiescent cells are partly diverted to macromolecule production in dividing cells. Cell metabolism has long been a focus of molecular biology; for the cancer field its study represents a return to original lines of inquiry after years of focus on the genetics of cell transformation and the oncogenes involved in signal transduction pathways. At the May 28, 2015, Hot Topics in Life Sciences symposium Cancer Cell Metabolism: Unique Features Inform New Therapeutic Opportunities, the speakers expressed hope that a synthesis of these two approaches will yield progress in cancer research.

Craig B. Thompson of the Memorial Sloan-Kettering Cancer Center reviewed the basics of cell metabolism. After the initial step in glucose metabolism—glycolysis, conversion of glucose to two molecules of pyruvate—mitochondrial oxidative phosphorylation usually proceeds to yield ATP. But even in the presence of oxygen, many cancer cells divert pyruvate to fermentation, producing lactate. This less rewarding mode of ATP production demands a relatively high rate of glycolysis. Otto Warburg described this shift toward “aerobic glycolysis” in cancer cells in 1924. The molecular and genetic basis of the Warburg effect, however, has only recently come to light. Contrary to Warburg’s hypothesis that mitochondrial defects necessitate this shift, most cancer cells maintain the ability to execute oxidative phosphorylation and do fully catabolize a small amount of glucose.

Cancer cells are genetically differentiated from normal cells, but it is now clear that the metabolic shifts they exhibit are also partly required for division of normal cells. In a quiescent cell, maximum ATP production yields enough energy for cellular machinery, and at least 50% of free energy is used for ion transport across the membrane. When a cell divides, glycolytic intermediates are diverted from the tricarboxylic acid (TCA/Krebs) cycle to reserve carbon and nitrogen for fatty acid synthesis and for production of nonessential amino acids. DNA replication demands de novo nucleotide synthesis, beyond the supply garnered from recycling pathways in a non-dividing cell. Ribose, serine, and glycine (byproducts of glucose metabolism), as well as glutamine for pyrimidine production, are needed for nucleotide synthesis.

cancer cells consume glucose and glutamine

cancer cells consume glucose and glutamine

http://www.nyas.org/image.axd?id=62a5b6cc-1a92-4740-9cb9-b4f027726c09&t=635738696433870000

Cancer cells consume glucose and glutamine at higher levels than normal cells; many oncogenes implicated in signaling cascades also regulate metabolism of these nutrients. Research in cell signaling and metabolism may produce more effective combination therapies to treat cancer. (Image courtesy of Craig B. Thompson)

Glutamine carbon is required for hypoxic cell viability

Glutamine carbon is required for hypoxic cell viability

glutamine-supplies-the-succinate-pool-through-oxidative-and-reductive-metabolism

glutamine-supplies-the-succinate-pool-through-oxidative-and-reductive-metabolism

Thompson noted that previously overlooked clues from cell biology research are fundamental to current work to understand the unique metabolism of cancer cells. Harvey Eagle, who is largely credited with establishing a protocol and eponymous growth medium for culturing mammalian cells, did much of his foundational work with the HeLa cell line, derived from a pancreatic tumor. He observed a key feature of proliferating cells’ metabolism when he found that these cells need to be cultured in a buffered solution supplemented with glucose and, to his surprise, high levels of the nonessential amino acid glutamine. In an anabolic cell where Kreb’s intermediates are diverted to biosynthesis, glutamine metabolism provides a means of anaplerosis. Indeed, some tumors are said to be “glutamine addicted” and cannot survive without exogenous glutamine. The pharmaceutical company Calithera seeks to exploit this property with a new drug, CB-839, that inhibits glutaminase. It is in phase I clinical trials for treating cancer.

Christian Metallo of the University of California, San Diego, has used metabolic tracing to show that the glutamine contribution to lipogenesis shifts in mammalian cells in an oxygen-dependent manner. Cells cultured under hypoxic conditions, which might mimic those experienced by cancer cells in a poorly vascularized tumor, shift to reductive carboxylation of α-ketoglutarate. This glucose and glutamine derivative is also critical in stem cells.Lydia Finley of the Memorial Sloan-Kettering Cancer Center linked α-ketoglutarate levels in embryonic stem cells to the maintenance of demethylation and pluripotency.

Thompson argued that metabolic shifts that define cancer cells are not a secondary consequence of transformation, as has long been thought. The most common genetic mutations that drive cancers are in proto-oncogenes and tumor suppressor genes, which regulate pathways that control cell division. The constitutive activation of the cell cycle and the loss of checkpoints, however, are not enough to drive unmitigated growth; the cell must also undergo metabolic transformation to meet the energetic and synthetic demands of growth. This hypothesis, although perhaps intuitive, has only gained prominence with observations linking metabolic genes to control by signal transduction pathways.

The most commonly mutated gene in cancers is KRAS. The KRAS protein, a GTPase, normally functions as a molecular switch, relaying signals received by receptor tyrosine kinases and other receptors of extracellular signals. Two of its main targets include the MAPK and PI3K signal transduction cascades. But many indirect targets of KRAS are involved in cellular metabolism, including glucose transporters that are positively regulated by the PI3K/Akt pathway. Glutamine-addicted tumors are often characterized by the oncogenic expression of Myc, a transcription factor that promotes the expression of glutamine transporters as well as metabolic enzymes needed for biosynthesis. Constitutively activated KRAS thus primes a cell to undergo aerobic glycolysis by ensuring a steady influx of glucose. Selina Chen-Kiang of the Weill Cornell Medical College showed that therapies targeting the cell cycle indirectly reduce PI3K activation in cancer cells. In collaboration with Pfizer, her research group has tested the Cdk4/6 inhibitor palbociclib in early-phase clinical trials in Mantle cell lymphoma (MCL) patients. Genetic and biochemical analysis of tumors from palbociclib-responsive MCL patients exhibited reduced glucose transporter expression. Palbociclib is currently being tested as a cancer therapy in five separate clinical trials.

Jon Blenis of the Weill Cornell Medical Center identified another common genetic hallmark of cancer linked to metabolism, activated mTORC1 (mTOR Complex 1) signaling. Pathways that activate this complex integrate metabolism by sensing levels of nutrients, such as amino acids leucine and glutamine. The complex then regulates glucose and glutamine metabolism, amino acid production, and lipid biosynthesis. Blenis’s group has screened for targets in the pathways to identify combination therapies for mTORC1-activated cancers. One combines the glutamine metabolism inhibitor BAPTES with the HSP90 inhibitor 17-AAG to reduce transformed cells’ ability to carry out aerobic glycolysis and confront oxidative stress. A novel downstream target of mTORC1, the kinase SPRK2, is another promising lead.

Each tumor arises from a unique sequence of genetic lesions. Does each also have a unique metabolic signature? Most conclusions on this topic are drawn from studying isolated cancer cell lines, but tumor cells may execute metabolism differently in vivoMatthew G. Vander Heiden of the Massachusetts Institute of Technology described rodent models of non-small cell lung carcinoma and pancreatic cancer, both driven by KRAS-activation and p53-knockout mutations. The first model had tumors characterized by increased glucose uptake; surprisingly, these tumors had elevated glucose catabolism through oxidative phosphorylation, in addition to elevated glycolytic metabolism. Glutamine tracing, however, showed almost no glutamine anaplerosis in vivo. But when explanted to culture conditions, cells from these tumors acquired glutamine dependence. In the pancreatic cancer model, no single nutrient was clearly favored as a metabolite. Albumin labeling experiments, however, showed that most of the pancreatic cancer cell biomass was derived from this extracellular protein.

It has long been assumed that extracellular protein is not a major fuel for most cells, but as Thompson observed, there is evidence that mammalian cells can draw on this energy source. Most cell culture media are supplemented with serum containing albumin, and the 0.74 mM concentration of albumin found in human plasma is equivalent to a 400 mM source of amino acids. The finding that cancer cells and cultured normal cells ingest extracellular protein through micropinocytosis has invigorated the field. The normal pathway to nutrient acquisition in slime molds, this process involves forming a vesicle around the extracellular contents and ingesting whatever is present in the surrounding media. The tumor cells in Vander Heiden’s pancreatic cancer model fed biosynthesis and anaplerosis through this unusual process of macropinocytosis and protein catabolism.

branched-chain amino acids are significant contributors to fatty acid synthesis in proliferating adipocytes

branched-chain amino acids are significant contributors to fatty acid synthesis in proliferating adipocytes

http://www.nyas.org/image.axd?id=7fdc9086-1a45-4711-a22d-a3ce9b6bdaef&t=635738696331830000

Using stable isotope tracers and mass spectrometry to quantify label incorporation, Metallo made the surprising observation that branched-chain amino acids are significant contributors to fatty acid synthesis in proliferating adipocytes. Cancer cells also catabolize protein through a lysosomal pathway to fuel biosynthesis. Inhibiting autophagy and protein catabolism in tumor cells could thus be new strategies for cancer therapies. (Image courtesy of Christian Metallo)

Thompson’s data show that mouse embryonic fibroblasts grown in leucine-depleted media cease proliferating. But their growth is rescued by the addition of albumin in excess of 3%. The addition of chloroquine to inhibit lysosomal proteolysis confirmed that albumin is metabolized via a macropinocytic mechanism; blocking the cell’s ability to form lysosomal vesicles abrogated the albumin rescue. Alec C. Kimmelman of Harvard Medical School explained that autophagy, another lysosome-dependent pathway, could be a therapeutic target in cancers such as pancreatic adenocarcinoma. Activated KRAS–driven pancreatic cancers have historically been among the most difficult to treat, with a 5-year survival rate of 6%. Kimmelman’s data show that genetic or pharmacologic inhibition of autophagy slows growth of pancreatic cancer cell lines and of tumors in genetically engineered mouse models. This work also demonstrates that autophagy has key roles in the metabolism of these tumors.

Altered metabolism facilitates the rapid proliferation of transformed cells; it is also implicated in metastasis and in the maintenance of pluripotency. Elena Piskounova of the University of Texas Southwestern Medical Center explained that successful metastasis, which is associated with worse cancer outcomes, is a relatively rare event; for every thousand cells that dissociate from a tumor, only one or two will successfully colonize a new site. Using a xenograft model with human melanoma cells introduced to immunocompromised mice, Piskounova showed that the limiting step in metastasis was cell survival in the circulatory system. Metabolic profiling revealed that these cells have high levels of oxidized glutathione and reactive oxygen species. Treatment of the xenografted mice with antioxidants increased the rate of metastasis, suggesting that, to survive, circulating tumor cells (CTCs) must overcome oxidative stress. Piskounova explained that cancer cells’ need for NADPH, a reducing molecule that helps cells combat oxidative stress, might be met through folate metabolism.

If it survives oxidative stress, a CTC must adapt metabolically to the target tissue it colonizes. Sohail Tavazoie of the Rockefeller University studies how colon cancer–derived cells colonize the liver. A screen for microRNAs that suppress colon-to-liver metastasis identified mir-483 and mir-551a, which targeted the brain-type creatine kinase (CKB). Further study revealed that this kinase is secreted from cells and then converts creatine to phosphocreatine in an ATP-dependent reaction. Transport of the phosphocreatine back into the cells provides a catabolic substrate to fuel cellular energy and biosynthetic needs. Drugs that promote oxidative stress or block folate metabolism, NADPH production, or creatine utilization hold promise as therapies to prevent metastasis.

The New York Academy of Sciences. Cancer Cell Metabolism: Unique Features Inform New Therapeutic OpportunitiesAcademy eBriefings. 2015. Available at: www.nyas.org/TumorMetabolism-eB

Click Chemistry in Biology and Medicine

Organizers: Peng Wu (Albert Einstein College of Medicine) and Jennifer Henry (formerly at The New York Academy of Sciences)
Keynote Speakers: Jim Paulson (Scripps Research Institute) and K. Barry Sharpless (Scripps Research Institute)Presented by the Chemical Biology Discussion Group

Reported by Megan Stephan | Posted November 21, 2014

click chemistry

click chemistry

http://www.nyas.org/image.axd?id=b9daf7c7-763f-4fe7-8b85-959be16e67e0&t=635513990247670000

Click chemistry is a new approach to synthetic organic chemistry that uses simple chemical building blocks and mild aqueous conditions to produce high-specificity ligands and labeling molecules for the investigation of biological systems. These reactions mimic those found in nature for building large complex molecules such as proteins, DNA, and RNA. Since its inception by K. Barry Sharpless, click chemistry has yielded several novel reactions that have been used to produce experimental tools and therapeutic agents, some of which are now in preclinical testing. The products of these reactions are particularly useful for investigating difficult-to-synthesize biological products such as glycans, and challenging, highly transient signaling activities such as those depending on redox reactions. On September 15, 2014, pioneers and young investigators in the field presented their recent work, providing a glimpse into the expanding possibilities of this synthetic methodology. The symposium, Click Chemistry in Biology and Medicine: New Developments and Strategies, was presented by the Academy’s Chemical Biology Discussion Group.

Lung Cancer

Advances in Current Treatment Modalities and Patient Classification

Organizers: Magdalena Alonso-Galicia (Forest Research Institute), Shashidhar S. Jatiani (Forest Research Institute), Huiping Jiang (Boehringer Ingelheim Pharmaceuticals), George Zavoico (HC Wainwright), and Jennifer Henry (The New York Academy of Sciences)
Speakers: Rolf Brekken (UT Southwestern Medical Center), Jessica S. Donington (NYU Langone Medical Center), Balazs Halmos (Columbia University Medical Center), Roy S. Herbst (Yale School of Medicine), and Suresh S. Ramalingam (Emory University)Presented by the Biochemical Pharmacology Discussion Group

Reported by Paul Riccio | Posted May 28, 2014

Like other cancers of the internal organs not often diagnosed until late stages of disease, lung cancer is among the deadliest. In the U.S., the 5-year survival rate after diagnosis is lower than 15%. Lung cancer is also among the most common cancers, in part because of the continued prevalence of tobacco smoking. The American Cancer Association estimates that in 2014, 224 210 people will be newly diagnosed with lung cancer and 159 260 deaths will be associated with the disease. On March 25, 2014, the Biochemical Pharmacology Discussion Group convened physicians and scientists for the Lung Cancer: Advances in Current Treatment Modalities and Patient Classification symposium, to discuss advances in treatment as well as new information about genetic heterogeneity that may inform future trials. Despite poor outcomes for current treatments, the speakers were optimistic that therapeutic innovations will gradually improve prognoses for this seemingly intractable disease.

From refinements in surgical techniques to drugs targeting specific oncoproteins, the range of precision therapeutic tools to combat lung cancer is growing. Several speakers cautioned, however, that technological innovation alone will not dramatically transform lung cancer treatment. Rather, physicians must tailor treatments for each patient and deploy tools discriminately, biopsying and sequencing each tumor, for example, and choosing the most appropriate drugs among many. Roy Herbst and Balazs Halmos both related adaptive treatments that resulted in several rounds of remission in patients. However, successes like these have been achieved in large medical centers where clinicians had access to drug trials. Adapting protocols for personalized medicine in a wide range of clinical settings remains challenging.

In his introduction to the symposium, Shashidhar S. Jatiani of the Forest Research Institute reviewed the sub-classification of lung cancer into small cell and non-small cell types. The former is a grim diagnosis: patients almost always present with advanced disease because metastasis occurs early. Chemotherapy is the standard treatment. More common, however, is a diagnosis of non-small cell lung cancer (NSCLC), which accounts for approximately 85% of new cases. The speakers focused on the treatment of NSCLCs, which usually arise in the epithelium of the branched lung, most commonly as an adenocarcinoma.

When NSCLC is identified as a pre-metastatic tumor, the most effective treatment is surgery. Jessica S. Doningtonof NYU Langone Medical Center explained that a balance must be achieved between complete removal of cancerous cells and preservation of lung function. The standard of care is removal of the lobe containing the tumor, one of five lobes in the lungs. A complete lobectomy is an invasive procedure, requiring the surgeon to break several ribs to access the thoracic cavity. The average age of patients at diagnosis is 70 years old, and many patients require substantial care to recover from such a surgery. But it has become possible to perform more precise surgery: rather than remove the lobe entirely, many surgeons now resect a minimal amount of tissue, directed by the branched morphology of the lung, in a procedure called a segmentectomy. In addition, the use of laparoscopic cameras in a technique known as video-assisted thoracic surgery (VATS) now limits the size of the incision to the circumference of the tumor itself. An increasing number of hospitals now support robot-assisted surgery using the da Vinci Surgical System, which can also be used to achieve less-invasive segmentectomies. Both techniques decreased morbidity and mortality when compared to open thoracic surgery. Although purchasing and maintaining a da Vinci system is a substantial investment, significantly less money is required for postoperative intensive care and respiratory therapy when VATS and robot-assisted surgery are used compared to open surgery.

New technologies in the operating room, such as the robotic da Vinci Surgical System pictured above, allow surgeons to remove malignant tissue more precisely. Laparoscopic and robot-assisted surgeries yield faster patient recoveries and fewer post-operative expenses. (Image courtesy of Jessica S. Donington)

http://www.nyas.org/image.axd?id=9c706d8a-56c0-4a41-a38c-1070e94d8301&t=635358375925400000

Inoperable tumors that arise close to the main airways, or in patients too frail to undergo surgery, are treated with radiation therapy. In an adaptation of a radiotherapy technique originally applied to brain tumors, lung tumors are now targeted more precisely and with higher doses of radiation using hypo-fractionated stereotactic body radiation therapy (SBRT). In the Netherlands, where practitioners have aggressively phased out older modes of radiation therapy in favor of SBRT, a greater than 36% increase in 8-month survival has been observed concurrent with the change.

Underlying the success of VATS, robot-assisted surgery, and SBRT is the theme that “less is more,” Donington said. Less healthy tissue is destroyed, less time and resources are required for patient recovery, and patients are ideally better prepared to undergo adjuvant therapy.

When the primary tumor has metastasized, as in more advanced cases, chemotherapy is often prescribed in addition to surgical or radiological interventions. Unfortunately, in most patients traditional chemotherapy regimens afford delayed progression at best and are rarely curative. No progress has been achieved in developing more potent chemotherapies or combinations of cytotoxic drugs for lung cancer in over ten years. In response, many physician-scientists, including symposium speakers Roy S. Herbst, Balazs Halmos, and Suresh S. Ramalingam, have begun studying the efficacy of new drugs targeting specific oncogenic pathways. Through whole exome sequencing of lung tumors, a portrait of the most common genetic aberrations has emerged. Mutations in KRAS have been known to occur in lung adenocarcinomas for at least ten years, and comprehensive sequencing efforts have additionally implicated oncogenes, including the receptor tyrosine kinases EGFR, MET, RET, NTRK1, ROS1, and HER2; the serine threonine kinase BRAF; and the atypical receptor tyrosine kinase ALK. In fact, only 37% of examined lung adenocarcinomas do not harbor mutations in any of these genes.

Molecular testing of biopsied lung tumors

Molecular testing of biopsied lung tumors

http://www.nyas.org/image.axd?id=b00258fa-70f3-4be6-a516-d78a44c89b97&t=635358376025530000

Molecular testing of biopsied lung tumors is necessary to match patients with the best therapeutic options. Through clinical trials and collaborative sequencing efforts, a comprehensive list of the mutations that drive lung cancer is emerging. As shown above in data reported by the Lung Cancer Mutation Consortium, these mutations are frequently in oncogenes, particularly receptor tyrosine kinases. (Image courtesy of Suresh S. Ramalingam)

Providing some historical perspective, Roy S. Herbst of Yale School of Medicine told participants that the first-generation receptor tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib entered the clinic in 1997, delivering modest response rates of less than 10%. Ten years later, with the emergence of deeper tumor exome sequencing, it became clear that responders were much more likely to harbor specific EGFR mutations, such as deletion of exons 19 or 21, which encode parts of the catalytic domain. Tumors with EGFR exon 19 deletion, in particular, exhibit susceptibility to erlotinib, which functions as a competitive inhibitor at the ATP binding site. Balazs Halmosof Columbia University Medical Center observed that based on the specificity of the TKIs, the conscientious clinician will need to become something of a “mutation aficionado,” to be able to match the most efficacious TKI to each patient. At present, such choices are largely confined to clinical trials because erlotinib, gefitinib, imatinib, and afatinib are the only TKIs approved for lung cancer. Physician training will be needed as more of these drugs achieve FDA approval. To illustrate the complexity of genetics-based drug choice, Herbst mentioned the BATTLE-2 clinical trial, which he oversees. It compares several TKIs and employs a full-time statistician to conduct a Bayesian learning method to help oncologists to make the best drug/tumor match.

Receptor tyrosine kinase (RTK) inhibitors may target the mutated pathways that manifest in many lung adenocarcinomas, but a considerable proportion of tumors do not exhibit obvious mutations. From a therapeutic perspective, therefore, drugs must be developed to target more general molecular pathways that are active in tumor cells. Suresh S. Ramalingam of Emory University reviewed one such strategy, which targets the heat-shock protein HSP90. Heat-shock proteins bind and stabilize client proteins, including oncoproteins, thus preventing their degradation through the proteasome. Drugs that inhibit HSPs, such as the second-generation HSP90 inhibitor ganetespib, should theoretically facilitate the indirect degradation of oncoproteins. Moreover, such drugs will only target cancer cells, because HSP90 remains at very low levels in healthy tissue. Ramalingam outlined an active phase III study of ganetespib, the GALAXY-2 trial.

The TKIs are indeed revolutionary tools in the field of molecular oncology, but frustratingly, these novel agents only delay disease progression and do not increase survival rates among lung cancer patients. Selective pressures in the tumor microenvironment favor either cells that acquire subsequent mutations or the activation of downstream effectors that thwart the loss of the RTK. As Halmos explained, these mutations often occur in the RTKs themselves. In the case of epidermal growth factor receptor (EGFR), insertions into exon 20, or a threonine to methionine substitution in a part of the protein encoded by exon 20, render the mutant receptor resistant to TKIs. The speakers speculated that combinations of drugs targeting several oncoproteins may circumvent the problem of tumor resistance, but available agents are limited and there are no obvious putative combination therapies.

Rolf Brekken of UT Southwestern Medical Center outlined the rationale for using immunotherapy to combat lung cancer. A hallmark of tumor cells is their evasion of immune detection, achieved in part by the presentation of phosphatidylserine (PS) in the outer cell membrane. In healthy cells, this phospholipid is confined to the inner leaflet of the cell membrane. When PS becomes externalized, as in normal apoptosis, PS receptors in macrophages that detect the dying cell trigger the release of immunosuppressive cytokines. Brekken hypothesized that if this process can be inhibited, an adaptive immune response might ensue. The monoclonal antibody bavituximab, developed by Peregrine Pharmaceuticals, targets glycoprotein-bound PS. Preclinical data using bavituximab to combat a rodent tumor model is encouraging, with tumors completely regressing in some rats. Brekken’s lab has observed several lines of evidence suggesting that an innate immune response occurred in bavituximab-treated rats, leading to the development of anti-tumor T cells. As several speakers noted, the best test of this therapy would be to reintroduce tumor cells to the rats and observe whether the cells are targeted and destroyed by an immune response. Such a result would be astonishing. Indeed, the potential of immunotherapy in cancer treatment has recently received considerable attention from the popular media. Several antibodies have entered clinical trials, including bavituximab, which is in a phase III NSCLC trial called SUNRISE.

From new developments in surgery and radiation therapy to a rapidly expanding collection of drugs in the field of molecular oncology, we are poised to improve the prognosis for many lung cancer patients. Key to success will be a continued emphasis on personalized medicine, augmenting the standard diagnostic regimen to include molecular testing to match each patient with a targeted therapeutic approach.

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