TUMOR INTRINSIC

OVERVIEW

Novel cancer therapies that exploit tumor intrinsic properties can be directed by tumor antigens or by tumor dependencies that profoundly impact cancer cell fate. Targeting antigens involves therapies directed against markers that are present on cancer cells but not on normal cells.1 Targeting tumor dependencies involves therapies directed against mechanisms and dependencies that are unique to the cancer.2


Tumor Antigen Targeting
  • The ideal tumor antigen would be a “tumor-specific antigen,” which is an antigenthat is solely expressed by malignant cells; tumor-specific antigens provide a unique target that will lead to maximal tumor elimination with minimal off-target toxicity.1
  • However, tumor-specific antigens are rare, as most antigens that are expressed by malignant cells are also found in normal tissues. Therefore, the more accurate designation of these antigens is “tumor-associated antigens (TAA)”, rather than tumor-specific.1
  • TAAs can be broadly categorized into three groups:1
    • Aberrantly expressed self-antigens
    • Mutated self-antigens
    • Tumor-specific antigens

BIOLOGY OF TUMOR-ASSOCIATED ANTIGENS1

  • (A)TAAs originate in various cellular compartments, including the nucleus, granules, cell membrane and cytoplasm. However, in order for effective antigen presentation to occur, (B) the TAA must localize to cellular compartments that facilitate antigen presentation.1
    • The abnormal expression of TAA by malignant cells, either through overexpression or aberrant localization, can lead to preferential presentation of TAA-derived immunogenic epitopes on the target cell surface.1

Therapeutic Potential1

  • A feature that makes a TAA ideal for immunotherapy is the dependency of the malignant cells on the expression of the TAA.
  • Targeting TAAs that drive the proliferation of the malignant clone will not only contribute to the reduction of the disease burden, but may also eliminate the underlying malignant clone/stem cell that must ultimately be eradicated for achieving cure.

Tumor Dependency:

The tumor dependency approach has produced new targeted therapies that may address one or more of the biological hallmarks of cancer that tumors exploit to proliferate, such as, resisting cell death (avoiding apoptosis) sustaining proliferative signaling, evading growth suppressors, and enabling replicative immortality.2 The ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation (cell replication), but also by the rate of cell attrition (cell death):2

  • Apoptosis, or programmed cell death, represents a major source of cell attrition.2
    • Sensors (intrinsic or extrinsic) are responsible for monitoring the extracellular and intracellular environment for conditions of normality or abnormality that influence whether a cell should live or die; these sentinels include cell surface receptors that bind survival or death factors.2
    • Effectors (capsases) are regulated by the sensors and ultimately carry out the execution of the death program through selective destruction of subcellular structures and organelles and of the genome.2
    • The BCL-2 family of proteins in the intrinsic apoptosis pathway are “sensors” or “regulators” that control cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP), leading to the irreversible release of cytochrome C, subsequent caspase (“effectors”) activation, and the resulting apoptosis.3
    • The TNF protein receptor superfamily in the extrinsic apoptosis pathway includes TRAIL receptors 1 and 2 (DR4 and DR5); when bound to their ligands, these receptors induce the ultimate activation of the downstream caspases leading to apoptosis.4,5
  • Epigenetic regulation, including acetylation and other histone modifications, control essential transcriptional regulatory processes in the cell.6
    • The BET family proteins associate with transcriptional activation through interaction with acetylated chromatin, therefore playing a key role as epigenetic regulators.7
    • Bromodomains, which are proteins with acetyl-lysine binding modules, function as the principal mediators of molecular recognition of acetylated chromatin and therefore have a key role in transcriptional activation.7
    • Bromodomains of BET proteins bind to acetylated chromatin during interphase but also remain attached to chromosomes during mitosis.6
    • BET proteins play a prominent role in cell proliferation.6

Therapeutic Potential

  • Acquired resistance to apoptosis is a hallmark of most, if not all, types of cancer.2
    • In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event.8
    • Dysregulation of the apoptotic pathways can not only promote tumorigenesis, but can also render cancer cells resistant to conventional anti cancer agents because, chemotherapy- and radiotherapy-induced killing of cancer cells is mainly mediated through activation of apoptosis.9
  • Overexpression of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-1) disrupts the dynamic balance of anti- and pro-apoptotic proteins, which may promote cancer cell survival.9,10
    • The overexpression of these proteins is seen in a wide variety of hematologic malignancies and solid tumors.9,11
    • The heterogeneity among tumors, even of the same type, necessitates a continued effort to further investigate mechanisms of apoptosis dysregulation in distinct cancer cell types.9
  • Strategies to inhibit anti-apoptotic BCL-2 proteins include reducing protein expression by targeting the corresponding mRNA with an antisense oligonucleotide compound as well as blocking anti-apoptotic activity by targeting at the protein level.9,10
    • There is interest in developing drugs that mimic the action of the BH3 domain by binding to one or more of the BCL-2-like proteins and triggering the apoptotic program.10
  • TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumors, therefore, inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumor onset, progression, and treatment resisitance.12
    • TRAIL can bind as a trimer to any of four membrane-bound and one soluble receptor, but only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) with intracellular functional death domains (DDs) can induce apoptosis of tumor cells.4
    • Studies have demonstrated that TRAIL-R1 and R2 receptor agonists (TRAs) are generally well tolerated and that TRAIL can selectively trigger apoptosis in tumor cells without affecting normal cells across a wide range of tumor types, including colorectal cancer, lung cancer, pancreatic cancer, acute myeloid leukemia and non-Hodgkin lymphoma.12-16
  • BET family proteins are involved in promoting aberrant oncogene expression in a variety of cancers.16-19
    • Overexpression and gain-of-function mutations of BET proteins can alter gene transcription, histone modification, DNA repair, and apoptosis.20
    • BET proteins serve to regulate the expression of important oncogenes, including those involved in apoptosis as well as cell cycle progression.7
    • Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes.20,21
    • Genetic rearrangements of BRD-containing proteins have been linked to the development of a number of extremely aggressive tumors.22
    • Small molecule inhibition of BET proteins has demonstrated promising activity in both solid and hematologic malignancies.7

Related Research

  1. Alatrash G, Crain AK, Molldrem, JJ. Chapter 7 – Tumor-Associated Antigens. In: Immune Biology of Allogeneic Hematopoeitic Stem Cell Transplantation. 2nd ed. Academic Press;2019:107-125
  2. Hanahan D, et al. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.  (image)
  3. Kale J, et al.  BCL-2 family proteins: changing partners in the dance towards death.  Cell Death Differ. 2018;25:65–80.
  4. Ghobrial IM, et al. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55(3):178-94.
  5. Lemke J, von Karstedt S, Zinngrebe J, Walczak H. Getting TRAIL back on track for cancer therapy. Cell Death Differ. 2014;21:1350-1364. 
  6. Garcia-Gutierrez P, Mundi M, Garcia-Dominguez M. Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B. J Cell Sci. 2012;125(Pt 15):3671-3680.
  7. Wadhwa E, Nicolaides T. Bromodomain inhibitor review: bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus. 2016;8(5):e620. 
  8. Ashkenazi A, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov.  2017;16:273-284. (image)
  9. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
  10. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
  11. Agarwal B, et al. Bcl-2 family of proteins in indolent B-cell non-Hodgkin's lymphoma: study of 116 cases. Am J Hematol. 2002;70(4):278-82.
  12. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 2008;8:782-798.
  13. von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 2017;17(6):352-366. 
  14. Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer. 2017;117(8):1089-1098. 
  15. Kretz AL, et al.  TRAILBLAZING Strategies for Cancer Treatment.  Cancers.  2019:11;456.
  16. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6(8):5501-5516. 
  17. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917. 
  18. Liu S, Walker SR, Nelson EA, et al. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol Cancer Ther. 2014;13(5):1194-1205. 
  19. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669-16674.
  20. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16(4):241-263.
  21. Jung M, Gelato KA, Fernández-Montalván A, Siegel S, Haendler B. Targeting BET bromodomains for cancer treatment. Epigenomics. 2015;7(3):487-501.
  22. Muller S, Filippakopoulos P, Knapp S. Bromodomains as therapeutic targets. Expert Rev Mol