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Pathways & Approaches

Research

Methodology for Cancer Research

We are dedicated to developing innovative cancer therapies targeted to specific molecular pathways. To do this, we focus on understanding how cancer cells evade apoptosis and the processes cancer cells need to survive, as defined by the landmark publication “The Hallmarks of Cancer.”1,2

AbbVie researchers are investigating a vast array of metabolic, signal-transduction and gene-regulation pathways to identify potential targets for therapeutic intervention. We are in late-stage development for agents targeting the B-cell receptor (BCR) signaling pathway, the B-cell lymphoma-2 (BCL-2) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) families of proteins, and the epidermal growth factor receptor (EGFR), CS1 (also known as CRACC, CD319, and SLAMF7), and the delta-like 3 (DLL3) cell-surface proteins.

Select Pathways & Targets

BCL-2

The BCL-2 family is composed of anti- and pro-apoptotic proteins.3 When working in concert, these proteins regulate apoptosis to maintain normal cellular homeostasis.3,4 Acquired resistance to apoptosis is a hallmark of most, if not all types of cancer.1

The principle function of the BCL-2 protein is to bind and sequester pro-apoptotic proteins, preventing them from initiating apoptosis.5 Overexpression of BCL-2 disrupts the dynamic balance of anti- and pro-apoptotic proteins, which may promote cancer cell survival.5 This overexpression is seen in a wide variety of hematologic malignancies and solid tumors.5

The role BCL-2 plays in tumor survival makes it a rational target for therapeutic intervention.4


PARP

A primary role of the PARP family of proteins is to detect single-strand DNA breaks and signal one of the enzymatic mechanisms for DNA repair.6,7

Tumor cells that are deficient in one or more of the DNA repair mechanisms may cause a heightened dependence on PARP-mediated repair, increasing the feasibility of PARP-inhibition as a target for treatment.6

By targeting PARP proteins, the tumor cell's ability to repair DNA damage is inhibited.This can lead to apoptosis in the cancer cell.7


EGFR

The EGFR is a transmembrane tyrosine kinase receptor that plays a role in cell division, cell differentiation and migration.8 Ligand binding to EGFR induces receptor dimerization and tyrosine autophosphorylation, which in turn elicits downstream activation and signaling.9

In cancer, EGFR is often mutated, amplified or overexpressed, resulting in abnormal receptor activation.10 For example, in the EGFRvIII  mutation (the most frequently occurring EGFR mutation in glioblastoma), the extracellular domain is truncated, resulting in ligand-independent constitutive activity.10

Increased signaling by EGFR contributes to the proliferative nature of the malignant cells, making EGFR an emerging target in cancer therapy.10


CS1

CS1, a SLAM family of proteins is a subset of the immunoglobulin (Ig) superfamily of receptors.11 These “self-ligand” proteins contain intra-cytoplasmic tyrosine residues that mediate signal transduction.11

CS1 may promote growth of normal B cells while inhibiting antigen-induced proliferation and cytokine production in T cells.11

Although CS1 expression is absent on most transformed hematopoietic cells, it is expressed on malignant plasma cells. In particular, most multiple myeloma cells highly express CS1.11


BTK

Bruton's tyrosine kinase (BTK) is a tyrosine kinase principally expressed in hematopoietic B cells, and is a key kinase in the B-cell receptor (BCR) signaling pathway.12,13

Activation of BCR initiates a signal cascade that results in the phosphorylation of several other signaling molecules, including BTK.13 Activation of BTK leads to the downstream activation of essential cell survival pathways, including those involved in proliferation, differentiation and antibody production, as well as those promoting B-cell migration and adhesion.13

In B-cell malignancies, such as CLL and mantle cell lymphoma (MCL), BCR activation is implicated in proliferation and survival of the malignant cell, as well as lymphoma cell homing and interaction with the tumor microenvironment.13

Inhibiting BTK may block the initiation of multiple BCR-activated survival pathways, reducing the tumor cell's ability to survive.13


DLL3

DLL3 is a protein that acts atypically as an inhibitory ligand of proteins in the Notch receptor family.14,15 During normal development, DLL3 localizes to the cis-Golgi and cytoplasmic vesicles, where it interacts with unprocessed full-length Notch1 and DLL1, preventing their localization to the cell surface.15,16

DLL3 is expressed at high levels on the cell surface in a large proportion of treatment-naïve as well as previously treated SCLC tumors (>80%), but has minimal-to-no expression in normal tissues or other non-neuroendocrine tumor types.15

Approaches & Technologies

In adult tissues, homeostasis is regulated and maintained by a balance between cell proliferation and apoptosis (programmed cell death), a highly controlled process for eliminating unneeded or damaged cells in response to developmental cues, cellular stress or injury.3

Apoptosis is also instrumental in safeguarding the integrity of the genome in response to severe DNA damage.6,7 A complex network of signaling pathways, activated via intracellular signaling or by extrinsic signals, act to promote or inhibit apoptosis.1

In most cancer cells, dysregulation of these pathways allows the cell to evade apoptosis, thus promoting tumor development and metastasis and conferring resistance to conventional anticancer agents.1,3 Pharmacological research in this area studies approaches that restore the cancer cell's ability to die in the face of acute damage include inhibiting antiapoptotic signaling throughout the network (BCL-2 inhibition)5 or inhibiting salvage pathways for DNA repair (PARP inhibition).7

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Epigenetic modifications are changes to the genome that do not involve a change in the nucleotide sequence. DNA methylation and histone modulation are key epigenetic modifications that regulate gene expression and central biological processes.17

Abnormal epigenetic modifications can contribute to tumorigenesis and resistance to cancer therapy by activating oncogenes, deactivating tumor suppressor genes and genes involved in the immune response, suppressing terminal differentiation, and affecting tumor heterogeneity.2,17-19

Pharmacological research in this area focuses on approaches to cancer treatment that include inhibiting the epigenetic mechanisms involved in histone acetyltransferase activity, chromatin remodeling and transcription regulation.19

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There are many natural immune effector mechanisms for tumor detection and elimination.20 Suppression, evasion, and even utilization of these mechanisms play a role in tumor growth and metastasis.2,20

Suppression of these mechanisms prevents the natural antitumor immune response.2

Evasion of these mechanisms can be accomplished through changes in the tumor cells that prevent recognition by immune cells. These changes include a loss of cell surface tumor antigens and a loss of sensitivity to complement, T-cell or natural killer (NK)-cell induced lysis.20

The utilization of normal immune functions within the tumor microenvironment prevents the expansion of tumor antigen-specific helper and cytotoxic T cells while promoting the production of proinflammatory cytokines.2,20

One pharmacological approach includes blocking inhibitory molecules on the surface of immune cells in the tumor microenvironment, which may potentially restore the immune cell's ability to recognize and eliminate tumor cells.20

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Tumor-initiating cells (TICs) are neoplastic cells that are able to regenerate detectable, sustained malignant populations after serial transplantations in xenograft models and consist of cancer stem cells and tumor progenitor cells.15,21 Rapid relapses after first-line therapy followed by multiple failed chemotherapeutic strategies suggested an underlying subpopulation of chemotherapy-resistant TICs in small cell lung cancer (SCLC).15,22 TICs have since been shown to be relatively common in SCLC, and may have a higher frequency in large-cell neuroendocrine carcinoma (LCNEC).15

SCLC TICs likely arise from normal pulmonary neuroendocrine cells (PNECs).15 The transcription factor achaete-scute homolog-1 (ASCL1) is critical for PNEC development and is highly expressed in many SCLC tumors.15,23 ASCL1 expression correlates with the tumor-initiating capacity of SCLC tumors.24

While activation of the Notch signaling pathway promotes oncogenesis in some tumor types, activation in neuroendocrine tumors suppresses tumor growth.14,25 DLL3 is an atypical inhibitory Notch ligand that appears to be a direct downstream target of ASCL1.14,15 Data suggest that DLL3 may also be associated with the neuroendocrine phenotype and may contribute to neuroendocrine tumorigenesis.15 While DLL3 is normally expressed only during development and not in adult tissues, DLL3 is expressed at high levels on the cell surface of >80% of small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) tumors.15

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Treating cancer with cytotoxic agents includes a risk of systemic adverse events. An antibody-drug conjugate (ADC) consists of a cytotoxin covalently linked to a monoclonal antibody (mAb) that recognizes an antigen differentially overexpressed on tumor cells. This allows for sensitive discrimination between malignant and healthy cells.26

Binding to the recognized antigen triggers internalization and degradation of the mAb, which releases the cytotoxin inside the cell. Ideally, ADCs may help provide a wider therapeutic index with potentially fewer side effects than “free” cytotoxic agents.26

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Bispecific antibodies (bsAbs) and/or “dual specificity” antibodies are engineered to recognize two different antigens or epitopes at the same time.27

Targeting two different receptors on the surface of the same malignant cell allows bsAbs to induce modifications of cell signaling more efficiently, potentially resulting in the inactivation of proliferation or inflammatory pathways.27

Targeting two receptors that are expressed on the surface of different cells allows bsAbs to help mediate the redirection of immune effector cells, such as NK cells and T cells, to tumor cells in order to potentially enhance tumor destruction.27

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References

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  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
  3. Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-8607.
  4. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
  5. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
  6. Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, Carey LA. Poly(ADP-Ribose) polymerase inhibition: “targeted” therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16:4702-4710.
  7. Plummer ER, Calvert H. Targeting Poly(ADP-Ribose) Polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13:6252-6256.
  8. Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006;33(4):369-385.
  9. Klein P, Mattoon D, Lemmon MA, Schlessinger J. A structure-based model for ligand binding and dimerization of EGF receptors. Proc Natl Acad Sci USA. 2004;101(4):929-934.
  10. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where the wild things are altered. FEBS Jour. 2013;5350-5370.
  11. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol. 2013;88(1):168-177.
  12. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296.
  13. Xia B, Qu F, Yuan T, Zhang Y. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies (Review). Onc Lett. 2015;10:3339-3344.
  14. Kunnimalaiyaan M, Chen H. Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist. 2007;12(5):535-42.
  15. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136.
  16. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20(5):905-916.
  17. Valdespino V, Valdespino PM. Potential of epigenetic therapies in the management of solid tumors. Cancer Manag Res. 2015;7:241-251.
  18. Falahi F, Sgro A, Blancafort P. Epigenome engineering in cancer: fairytale or a realistic path to the clinic? Front Oncol. 2015;5:22.
  19. Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54(5):716-727.
  20. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23 Suppl 8:viii6-viii9.
  21. Williams SA, Anderson WC, Santaguida MT, Dylla SJ. Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Lab Invest. 2013;93(9):970-982.
  22. Codony-Servat J, Rosell R. Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res. 2015;4(6):689-703.
  23. Meder L, König K, Ozretić L, et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer. 2016;138(4):927-938.
  24. Jiang T, Collins BJ, Jin N, et al. Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res. 2009;69(3):845-854.
  25. Takebe N, Nguyen D, Yang SX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther. 2014;141(2):140-149.
  26. Bouchard H, Viskov C, Garcia-Echeverria C. Antibody-drug conjugates—a new wave of cancer drugs. Bioorg Med Chem Lett. 2014;24(23):5357-5363.
  27. Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8:130.