Presentation on metastatic castration resistant prostate cancer

1. Metastatic Castration Resistant
Prostate Cancer(mCRPC)
National Institute of Pharmaceutical Education and Research
S.A.S Nagar, Mohali,Punjab(India)-160062
Presented by:
ISHFAQ AHMAD BHAT
18PCM2784
M.S(Pharm) 1st semester
Department of Pharmacology and Toxicology
1

2. Flow of Presentation
 INTRODUCTION
 ETIOLOGY AND PATHOGENESIS
 MOLECULAR MECHANISM OF RESISTANCE
 METASTASIS TO OTHER ORGANS
 MANAGEMENT OF METASTATIC CRPC
 LIMITATIONS TO CURRENT CANCER THERAPY
 DRUGS IN CLINICAL TRIALS
 NEW TARGETS AND APPROACHES
 CONCLUSIONS
2

3. INTRODUCTION
 Prostate cancer affects the prostate gland, the gland that produces
some of the fluid in semen and plays a role in urine control in men.
 2
nd
most common cancer and 5th leading cause of cancer mortality
in men.
 In 2017, the American Cancer Society predicts around 161,360 new
diagnoses of prostate cancer, and that around 26,730 fatalities.
 In India, PCa is the 2nd leading among males in large cities like Delhi,
Kolkata,Pune,and Thipuram and 3rd leading in cities like Banglore, and
Mumbai.
3
Pernar et al, Cold Spring Harb. Perspect. Med. a030361.

4. Cont..
 Castrate-resistant PCa (CRPC) is disease progression despite androgen-
deprivation therapy (ADT) and may present as one or any combination of a
continuous rise in serum levels of prostate-specific antigen (PSA), progression of
pre-existing disease, or appearance of new metastases.
 Advanced Pca ,previously called as hormone-resistant Pca(HRPC) and androgen
insensitive Pca is now named more precisely as “Castration- resistant” pca as it
includes intracrine and paracrine androgen production ,which is main cause of
resistance of pca cells to testosterone suppression therapy.
 CRPC is spectrum of diseases ranging from elevated PSA levels without
metastases/symtoms to metastases despite ADT
 Bone metastasis occur in 80% of men with CRPC,and can produce significant
morbidity ,including pain, pathologic fracture, spinal cord compression, and
bone marrow failure(SREs).
4
Hotte and Saad; Can Urol Assoc J. 2010 Dec; 4(6): 380–384

5. Symptoms
 Symptoms during the early stages of prostate cancer
 Frequent urges to urinate, including at night
 Difficulty commencing and maintaining urination
 Blood in the urine
 Painful urination and, less commonly, ejaculation
 Difficulty achieving or maintaining an erection may be difficult.
 Symptoms during the advanced stage
 Bone pain, often in the spine, femur, pelvis, or ribs
 Bone fractures
5
Joelle El-Amm et al; Ther Adv Med Oncol. 2013 Jan; 5(1): 25–40

6. ZONAL ANATOMY
6
Niranjan et al, N ature Reviews Urology volume 15, pages627–642 (2018)

7. ETIOLOGY
 Factors recognized as contributors to risk of PCa include;
 Dietary factors
 Genetic factors
 Medication and infections
 Sexual activity
7
Murtaza Mustafa et al; Journal of Dental and Medical Sciences, Volume 15, Issue 6 Ver. II
(June. 2016), PP 04-11

8. PATHOGENESIS
8
Packer JR .et al 2016
Processes;
Oxidative stress,
Inflammation,luminal
and basal proliferation
Molecular changes;
Upregulation of Bcl-2
and GSTP1
Downregulation of
NKX3.1,PTEN and
CDKN1B
Processes;
Luminal cell
hyperproliferation,
teleromerase shortening
Molecular changes;
ETS transcription factor
dysreg.NKX3.1loss,SPOP
mutation,TMPRSS2 ERG
fusion
Processes;
LCH, loss of basal
epithelia,basement
membrane
breakdown,immune cell
infiltration
Molecular changes;
Telomerase
activation,PTEN
deletion,RB1 loss

9. William G. Nelson et al; N Engl J Med 2003;349:366-81
Molecular events in pathogenesis of
prostate cancer
9

10. MOLECULAR MECHANISM OF
CASTRATION RESISTANCE
 The mechanism by which castration resistance occurs is
through many different types of somatic changes,
including__
 1.Increased AR expression
 2.Gene amplification
 3.Point mutations
 4.Increased conversion of adrenal androgens to DHT
 5.de-novo synthesis & upregulation of CYP17A1 to augment
production of androgens
 6.Production of AR splice variants.
10
Attard G et al; Annals of Oncology, Volume 26, Issue 8, 1 August 2015, Pages 1589–1604,

11. Castration Resistance
11
William G. Nelson et al; N Engl J Med 2003;349:366-81

12. Metastasis to other organs
 CRPC predominantly spreads to bones i.e.,bones mostly metastatized.
 First pelvic lymphnodes sites in bone including;
 1.illiac crests
 2. sacrum wings
 3. L1 to L5, T8 to T12 vertebrae
 4. ribs, manubrium, humeral heads and femoral neck.
 Cancer cells(15-30%) travelling through the BATSON PLEXUS OF LUMBAR SPINE.
 Defining Factors controlling homing of bone metastasis:
 1. Pagets “seed and soil” hypothesis of metastasis
 2. Ewings hypothesis-----anatomy of vasculature & lymphatics.
 Molecular Factors: Chemokines and integrins
12
Frieling JS et al; Cancer Control. 2015 Jan; 22(1): 109–120

13. Management of mCRPC
 Castrate-resistant prostate cancer (CRPC) is a form
of advanced prostate cancer that is resistant to
medical or surgical treatments to lower testosterone
levels and has spread to other parts of the body
 Over 80% of men with CRPC will progress to
metastatic castrate-resistant prostate cancer
(mCRPC), with progression being quite rapid in over
half of patients.
13
Sridhar et al. 2014, Eur. Urol. 65: 289–299

14. Diagnosis and Imaging of
mCRPC
 1.PSA(prostate specific antigen) screening-------to monitor the
progression of disease
 2. Digital rectal examination(DRE)-----------to test aymptomatic men for
prostate cancer
 3.Cystoscopy-----------shows the urinary tract from inside of bladder
 4.Transrectal ultrasonography-------creating an image of prostate gland
 5.Biopsy----------the only test that can fully confirm the diagnosis of PCa.
 Radio labelled Choline Positron Emission Tomography(PET-CT)
 PSA has been a mainstay and continued unmatched utility despite the
abundance of potential biomarkers
14
Jakobsen et al., 2016.

15. Treatment Strategies
1. Abiraterone acetate 1. Docetaxel 1. Sipuleucel-T 1. Radium-223
2. Orteronel 2. Cabazitaxel 2. Prostvac-VF
3. Galeterone 3. zoledronic acid 3. Pilimumab
4. Enzalutamide 4. Nivolimab
5.Denosumab
15
TREATMENT STRATEGIES
HORMONAL
THERAPY
CHEMOTHERAPY IMMUNOTHERAY
RADIOPHARMACE
UTICALS

16. Drug Target Effect Reference
Abiraterone
acetate
CYP17A1 Reduces circulating testosterone
levels
de Bono JS et al., 2011, N Engl J
Med.
Ryan CJ et al., 2013, N Engl J
Med.
Cabazitaxel Microtubules Microtubule stabilization,
interrupts cell cycle
de Bono JS et al., 2010, Lancet.
Denosumab RANKL Decreases bone resorption Fizazi K, 2011, Lancet.
Docetaxel Microtubules Microtubule stabilization,
interrupts cell cycle
Petrylak DP et al., 2004, N Engl J
Med.
Enzalutamide AR AR antagonism, prevents signaling Tannock IF et al., 2004, N Engl J
Med.
Radium-223 Bone Localized radiation Parker C et al., 2013, N Engl J
Med.
Sipuleucel-T Ex vivo activation of PBMCs via
GM-CSF and PAP
T-cell activation Kantoff PW et al., 2010, N Engl J
Med.
Zoledronic acid Osteoclasts Decreases bone resorption Tannock IF et al., 2004, N Engl J
Med.
Table 1: Approved Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer
AR = androgen receptor, GM-CSF = granulocyte-macrophage colony-stimulating factor, PAP =
prostatic acid phosphatase, PBMC = peripheral blood mononucleated cell, RANKL = receptor activator of
nuclear κB ligand.
16

17. Current cancer therapy is full of
limitations
LIMITATIONS TO HORMAL THERAPY
 Toxicity in rapidly dividing normal tissues -------bone marrow and gastrointestinal tract resulting inside effects implicating its nonspecificity
 Resistance to hormonal therapy:
 1.Increase AR receptor expression
 2. mutations in genes
 3. AR splice variants
 4. ↑sed testosterone production by cancer cells.
LIMITATIONS TO CHEMOTHERAPY
 Resistance development
 1. tubulin alterations
 2. increased expression of MDR genes
 3.epithelial mesenchymal transition
 4.expression of AR splice variants AR-V7
LIMITATIONS TO IMMUNOTHERAPY
 Physical properties and pharmacokinetics of the mAbs made them difficult to penetrate the tumor tissue efficiently and homogeneously.
 Immune escape due to ineffective FCγR binding and immunosuppressive muicroenvironment leads to reduced therapeutic efficacy.
17
Galletti G et al; Cancer Treat Rev. 2017 Jun;57:16-27.

18. Table 2: Experimental Therapies for the Treatment of Metastatic Castration-
Resistant Prostate Cancer
Drug Target Effect Study Results References
Cabozantini
b
c-METVEGF-R2 Inhibits tyrosine
kinase activity
Partial resolution of
bone lesions, decreases
number of CTCs,
decreases pain
Smith DC et al., 2013, J Clin Oncol.
Custirsen Clusterin Improves response
to docetaxel
Extended median
survival, extends PFS,
improves PSA declines
Saad F et al., 2011, Clin Cancer Res.
Ipilimumab CTLA-4 T-cell activation Ongoing Slovin SF et al., 2013, Ann Oncol.
Gerritsen WR et al., 2012, J Clin
Immunol.
Nivolumab PD-1 T-cell activation Ongoing Topalian SL et al., 2012, N Engl J
Med.
Orteronel CYP17A1 (17,20
lyase activity)
Reduces circulating
testosterone levels
Decreases number of
CTCs, improves
radiographic PFS
De Wit RFK et al., 2014, J Clin Oncol.
Dreicer R JR et al., 2014, J Clin Oncol.
Prostvac-VF Delivery of PSA
transgene
T-cell activation Improves median
survival
Kantoff PW et al., 2010, N Engl J
Med.
Gulley JL et al., 2010, Cancer
Immunol Immunother.
Tasquinimo
d
Thrombospondin
S100A9
Antiangiogenic,
reduces MDSC
Improves median PFS,
stable bone alkaline
Osanto S et al., 2013, Future Oncol.
Pili R et al., 2011, J Clin Oncol.
18

19. Sr.
no.
Drug Target Phase Sponsor Identification No.
1 Pembrolizumab(
MK-3475)
IgG4 blocker 2 ICR UK NCT03506997
2 CPI-1205 EZH2 INHIBITOR 2 Constellation NCT03480646
3 BEZ235 Pan-PI3K/mtor 1 Novartis Pharmaceuticals NCT01634061
4 BKM120 Pan-PI3K 1 Novartis NCT01634061
5 Olapariv PARP 3 Astrazeneca NCT02987543
6 eFT508 MNK1/MNK2 2 Effector Therapeutics NCT03690141
7 TRC105 Angiogenesis
inhibitor
2 NCI NCT01090765
8 GS5829 BETT 1 Gilead Sciences NCT02607228
9 AP1930 Dendritic Cell 1 Ballicaum Pharmaceutical NCT00868595
10 Ipilimumab CTLA4 1 NCI NCT00064129
Drugs in Clinical Trials:
19
https://clinicaltrials.gov/

20. New Targets and Approaches:
 Blocking expression of X-linked inhibitor of apoptosis gene(XIAP).
 Activation of Macrophage cytokine-1/P53 pathway
 Inhibition of AR gene overexpression
 Inhibition of steroidogenesis by blocking CYP11A enzyme
 Blocking expression of FKBP5 gene which is overexpressed in crpc
 Blocking gene expression coding for CYP17A1
 Activation of Retroblastoma(Rb1/2) & TP53 tumor suppressor genes
 Blocking expression of ZEB1 and TWIST1 genes
 Inhibition of Rac- -serine/ threonine PK (Akt/PKB) pathway.
20

21. Conclusions:
 1. Drug therapies approved by FDA increase life expectancy of
patients but are not curative.i.e, mCRPC is incurable.
 2. Onset of resistance is one of the primary roadblocks to the extension
of survival rates.
 3. Efforts directed towards ablating AR activity are likely to be fruitful.
 4. Thorough understanding of how drug resistance develops will lead to
improved treatment strategies.
21

22. 22