10. Cancer Therapeutics

• Nuclear receptors


  • Implicated in many cancers via multiple mechanisms
  • Retinoic acid receptors are important therapeutic targets in Acute Promyelocytic Leukemia
  • Estrogen receptor alpha (ERa) is an important therapeutic target in a subset of breast cancers
  • Nuclear receptors are atypical pharmacological targets
  • Androgen receptor is an important therapeutic target in advanced prostate cancer
  • Epigenetic coregulators may represent novel therapeutic targets in cancer
• Carcinogenesis: Epigenetic Silencing of Tumor Suppressor Genes
• Coregulator dysfunction plays an important role in carcinogenesis by effecting the epigenetic silencing by DNA methylation of tumor suppressor loci including the RARb2 gene
• Over-expression of NCOA3/SRC3/AIB1 is found in breast cancer and is believed to potentiate the growth enhancing actions of estrogens on breast cancer cells
• Androgen receptor is essential for prostate cancer development
• PML-RARa fusion oncoprotein inappropriately recruits corepressors
• Evidence that coactivator defects can underlie numerous hormone resistance syndromes

  • Androgen Insensitivity
  • Thyroid hormone resistance
  • Diabetes (Type II)...a role for PGC1 coactivator family?
  • PPAR gamma helix12 mutation found in severe insulin resistance, Diabetes, hypertension
• Established roles for nuclear receptors, coregulators coactivators / corepressors in

  • Hypertension
  • Diabetes / metabolic syndrome
  • Cancer
• What the pharmaceutical industry sees

  • NR modulators / agonists / antagonist
  • Coregulator inhibitors
• PML:RARa fusion oncoprotein


  • Homodimerizes
  • Increases recruitment of repressive complexes (HDACs, DNA methyltransferases)
  • Represses transcription of pro-differentiation genes
• PML:RARa repression can be relieved by pharmacological doses of retinoids alone or in combination with AsO3
• Absence of agonists RXR:RAR represses genes
• Retinoid agonists activate RXR:RAR target gene expression
• PML:RARa homodimers repress genes by HDACs and DNMTs
• Pharmacological Retinoids relieve PML:RARa repression
• Retinoids induced differentiation of malignant blasts: curative intent
• All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)
• SERMs: Selective Estrogen Receptor Modulators


  e.g. Tamoxifen
• Tamoxifen


  • Acts as an estrogen receptor alpha (ERa) antagonist in mammary tissue
  • Possesses (ERa) agonist activity in uterine tissue
• This appears to violate a core principle of pharmacology that a drug which is specific for a unique target protein should have the same effects in all tissues where the target protein is expressed
• Now we understand that NRs are ligand sensors rather than effectors of transcriptional output we can think of mechanisms which may contribute to this tissue specific effects of drug
• The role of NCOA1 (also called SRC-1) in enhancing ERa signaling
• Coassociation of estrogen receptor and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence
• Metastatic Progression with Resistance to Aromatase Inhibitors Is Driven by the Steroid Receptor Coactivator SRC-1
• Prostate Cancer


  • Prostate cancer is very common
  • 1 in 7 men will be diagnosed with prostate cancer
  • 1 in 4 men African, African-American and Afro-Caribbean men will get PCa
  • Diagnosis is generally via PSA screening and biopsy
  • Histological sub-types of PCa
  • Androgen responsive adenocarcinoma is the most commonly diagnosed
  • Neuroendocrine (NE) PCa is much rarer
  • Treatment emergent NE-like disease is increasingly common
• Curative therapy for organ-confined disease

  1. Surgery (often robotic assisted) for organ confined cancer

  2. External Beam Radiotherapy for organ confined cancer
• There is NO CURATIVE THERAPY for metastatic and hormone refractory/castrate resistant prostate cancer
• Therapy for locally advanced and metastatic disease

  1. Androgen deprivation therapy (ADT)

  2. Radiation therapy

  3. Palliative chemotherapy (taxane and corticosteroid)
• AR mutation and aberrant splicing contributes to ADT-resistance in PCa
• AR mutations in the LBD are also a mechanism of ADT-resistance
• Potential for Epigenetic Therapies which inhibit AR-coregulator complex