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Targeted Therapies For Breast Cancer

Presented By: Anvita Jadhav

Final Year B.Pharm 29/11/2013

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Clavicle

Second Rib

Fat

Lactiferous Sinus

Lactiferous Duct

Gland Lobules

Fat

Pectorals Major Muscle

Anatomy of the Female Breast

The breast is a modified skin appendages which functions in the females during lactation.

There are two types of tissue components: Epithelial and Stromal

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Breast Carcinoma

Non-invasive Carcinoma Invasive Carcinoma

a) Invasive Duct Carcinoma: 70% cases.b) Invasive Lobular Carcinoma: 5% cases.c) Medullary Carcinoma: 1% cases.d) Colloid Carcinomae) Papillary Carcinomaf) Tubular Carcinoma:g) Adenoid Cystic Carcinomah) Secretory (Juvenile) Carcinomai) Inflammatory Carcinomaj) Carcinoma with Metaplasia

a) Intraductal carcinoma b) Lobular carcinoma

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Receptor Overexpression Specific for Breast Cancer

Receptors

Hormone receptor (HR)

ER

ER+ve ER-ve

PR

PR+ve PR-ve

Tyrosine Kinase Receptor

HER2

HER2+ve HER2-ve

Triple negative breast cancer (TNBC)

Triple-negative breast cancers are ER –ve, PR –ve and HER2-ve, hence called as triple negative breast cancer (TNBC).

Less number of therapies are available for TNBC.

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Globally, Breast cancer accounts for 23% of the total cancer cases and 14% of the cancer deaths in females.

The cases are expected to increase by 26% by 2020

In India, premenopausal patients are about 50% of all patients.

A significant proportion of Indian breast cancer patients are younger than 35 years of age.

More than 80% of Indian patients are younger than 60 years of age.

It constitutes >30% of all cancers in females of Delhi, Mumbai, Ahmadabad, Kolkata, and Trivandrum.

Breast Cancer Statistics

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Surgery

Radiotherapy

Hormonal therapy

Chemotherapy

Treatments

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Targeted Cancer Therapies

Drugs or other substances that block the growth and spread of cancer by

interfering with specific molecules involved in tumor growth & progression.

Most researchers consider it as new approach to treating breast cancer that targets the cell signaling pathways of cancer cells.

More selective for cancer cells.

Blocking of signals help to stop cancer progression and may induce cancer cell death through apoptosis.

The development of targeted therapies requires the identification of good targets.

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In this seminar, we are going to study breast cancer therapies which are targeted for following targets:

Tyrosine Kinases Receptors

Steroid Receptor Coactivators (SRC)

Mammalian Target of Rapamycin (mTOR) & Phosphoinositide 3-kinase (PI3K)

Poly-{adenosine diphosphate (ADP)-ribose} polymerase (PARP)

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Class of enzymes which are responsible for phosphorylation of tyrosine residue on

targeted proteins.

Stimulate multiple signaling pathways responsible for basic cells functions.

Several oncogenic tyrosine kinases have been detected in human malignancies. There

are two families of tyrosine kinases- Transmembrane receptor kinases & Cytoplasmic non-

receptor kinase

a) Transmembrane kinases receptor :

Human Epidermal Receptor (HER)

Insulin like Growth Receptor (IGFR)

Fibroblast Growth Factor Receptor (FGFR)

Vascular Endothelial Growth Factor Receptor (VEGFR )

Platelet-derived Growth Factor Receptor (PDGFR)

b) Cytoplasmic non-receptor kinase: Steroid Receptor Coactivators (SRC)

Tyrosine Kinases (TKs)

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Multiple signaling pathways involved in the development, growth, and survival of breast cancer cells

mTOR/PI3K/Akt Pathway

IP3/DAG Pathway

Ras/MAPK Pathway

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o ErbB proteins are a four-member family of highly homologous receptor tyrosine

kinases comprised of ErbB1 (EGFR, HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4

(HER4).

o It is also known as ErbB1/HER1, is essential for growth and differentiation of epithelial

cells.

o The expression of EGFR, ligands, and their activating proteases in breast cancers has

been intensively studied.

Epidermal Growth Factor Receptor Targeting Monoclonal Antibodies:Agent Class of compound Stages

IMC-C225 mAb Phase II

ABX-EGF mAb Phase II

Human Epidermal Receptors (HER)

Epidermal Growth Factor Receptor (EGFR)

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The HER2 gene is amplified in approximately 20%-30% of breast cancers.

Overexpression HER2 found in breast cancer cells which has also been associated with

resistance to chemotherapy and hormone therapy.

HER2 target is present in a very high proportion of tumor cells

Human Epidermal Receptor 2 Targeting Monoclonal Antibodies: 

Agent Class of compound Stages

Trastuzumab mAb Approved

Trastuzumab–DM-1 mAb-toxin conjugate Approved

Human Epidermal Receptor 2(HER2)

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Trastuzumab Trastuzumab DM 1

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Compound Selectivity invitro IC(Nm) StagesEGFR HER2

ZD1839, Gefitinib 27 3700 Marketed

OSI-774, Erlotinib 2 350 Marketed

GW572016, Lapatinib 11 9 Marketed

CP-724714 4300 8 Phase II

Arry-334543 7 2 Phase II

CI-1033, PD183805, Canertinib

0.8 19 Phase II

BIBW-2992 0.5 14 Phase II

AV-412, MP-412 1 18 Phase I

AEE788 6 6 Phase II

EKB-569, Pelitinib 39 1200 Phase II

HKI-272, Neratinib 92 59 Phase II

BMS-599626 22 32 Phase I

Selected HER Family Tyrosine Kinase Inhibitors:

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IGF system is composed of

↑ circulating levels of IGF-I are associated with a greater risk of breast cancer in premenopausal women, with an especially high risk among those younger than 50 years.

↑ IGFs resists apoptosis in response to chemotherapy and radiation.

IGFBPs is activated by the estrogen, which itself activates expression of IGF-I.

Insulin-like Growth Factor Receptor (IGFR)

IGF system

Ligands

IGF1 IGF2

Receptors

IGF1R IGF2R

Binding Proteins

6 IGFBPs

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Insulin-like growth factor 1 receptor (IGF-1R) Targeting Agents:

Agents Regimen Stages

IGF-1R Antibodies

CP-751,871 Docetaxel Phase II

Exemestane Phase II

Single agent Phase I

AVE1642 / EM164 Faslodex Phase II

IMC-A12 (Cixutumumab)

Temsirolimus Phase I/ II

Capecitabine and Lapatinib Phase II

AMG 479 Exemestane or fulvestrant Phase II

MK-0646/h7C10

(Dalotuzumab)

Single Regimen Phase II

Ridaforolimus Phase II

Ridaforolimus and exemestane Phase II

Dual IGF-1R–insulin receptor inhibitor

BMS‑754807 Trastuzumab Phase I/ II

Letrozole Phase II

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The fibroblast growth factor (FGF) consist of 18 ligands.

FGF1 & FGF23 signal through four high affinity fibroblast growth factor receptor (FGFR1 to FGFR4).

Under physiological conditions, the highly complex FGF signaling pathway is tightly regulated.

The deregulation of FGF signaling to development of cancer, promoting cancer cell proliferation, survival and migration.

Fibroblast Growth Factor Receptor (FGFR)

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Drug class Drug name Target Stages

1st generation TKIs

TKI258 (Dovitinib) FGFR, PDGFR & VEGFR

Phase III

BMS54021 (Brivanib) FGFR & VEGFR Phase II

BIBF 1120 FGFR, PDGFR & VEGFR

Phase III

Ponatinib ABL, FGFR, PDGFRα, FLT3 & VEGFR2

Phase II

E7080 FGFR, PDGFR, VEGFR, KIT, RET

Phase I

E3810 FGFR1& VEGFR1 to VEGHR3 inhibitor

Phase I

Sulfatinib FGFR & VEGFR inhibitor

Phase I

Fibroblast Growth Factor Receptor Targeting Agents:

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Drug class Drug name Target Stages

2nd generation TKIs

AZD 4547 Selective FGFR1, FGFR2 & FGFR3 inhibitor

Phase II

BGJ398 Selective pan- FGFR inhibitor

Phase I

FGFR antibodies IMC-A1 FGFR1-IIIc-specific antibody

Preclinical

GP369 FGFR2 blocking antibody

Preclinical

PRO-001 FGFR3-specific blocking antibody

Preclinical

R3Mab FGFR3-specific antibody

Preclinical

FGFR ligand traps

FP-1039 FGF ligand traps (blocks multiple FGFs)

Phase I

Fibroblast Growth Factor Receptor Targeting Agents:

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VEGF overexpression is common in breast cancer.

Bevacizumab (Avastin; Genentech), a humanized monoclonal antibody against VEGF,

was granted accelerated approval in the US for the first-line treatment of MBC in

combination with Paclitaxel in 2008.

1st generation tyrosine kinase inhibitor; which also targets VEGFR are shown in

previous table.

Selected additional VEGF-targeted therapies:

Aflibercept or VEGF Trap is an antiangiogenic peptide-antibody fusion containing

portions of human VEGF receptor 1 and 2.

Vascular disrupting agents (eg, Ombrabulin; Sanofi-Aventis) another class of

antiangiogenic therapy, are under clinical trials for MBC.

Vascular Endothelial Growth Factor (VEGF)

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PDGFR is expressed in most breast tumors.

The individual PDGF chains have different affinities for the two receptors- PDGFR α &

PDGFR β.

PDGFR α has high affinity for PDGF -A, -B, and -C, whereas PDGFR β has high

affinity for PDGF -B and –D.

Induces angiogenesis by up-regulating VEGF production.

1st generation TKs; which also targets PDGFR are shown in previous table.

Platelet Derived Growth Factor (PDGFR)

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SRCs are small proteins of 160 kDa non-receptor tyrosine kinase and include SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2) and SRC-3.

SRC may play a significant role in tumor progression and spread.

SRC interact receptor tyrosine kinases (e.g. HER family), integrins, steroid hormone receptors, including the estrogen receptor.

Steroid Receptor Coactivators (SRC) Inhibitors:

Agents Stages Regimen

Dasatinib Phase I/II Fulvestrant and MK‑0646

Bosutinib Phase II Single Agent

Saracatinib Phase II Vs Zoledronic

Steroid Receptor Coactivators (SRCs)

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mTOR is a member of the cellular mTOR/PI3K/Akt pathway. A high proportion of breast tumors exhibit constitu tive activation of the mTOR pathway.

Rapamycin is a macrolytic lactone produced by Streptomyces hygroscopicus, which has immunosuppressive, antimicrobial, and antitumor properties. Rapamycin targets a principal protein that was named mTOR. Two mTOR complexes have been identified: mTORC1 and mTORC2 of cell growth and proliferation, cell metabolism, angiogenesis, and apoptosis.

New agents are being developed that can inhibit both mTORC1 and mTORC2.

Mammalian Target of Rapamycin (mTOR)

Phosphoinositide 3-kinase (PI3K)

Three classes of PI3K enzymes, designated I to III, have been identified; members of PI3K class I have been implicated in the mTOR pathway

PI3K can be key target that, if effectively inhibited, could improve outcomes.

24 The mTOR/PI3K/Akt pathway

PI3K inhibitor

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Drug Drug class Stage of development

Sirolimus(Rapamycin)

mTOR inhibitor Approved

Everolimus (RAD001)

mTOR inhibitor Approved in 2012 for postmenopausal women with advanced HR+/HER2- breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole

Ridaforolimus(deforolimus)(AP23573)

mTOR inhibitor Phase III clinical trials

PP242 mTOR inhibitor Preclinical

BN107 mTOR inhibitor Preclinical

mTOR inhibitors:

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Sirolimus (Rapamycin)

Everolimus

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PI3K selective inhibitors:

Agents Company Stage

PX-866 Oncothyreon Inc Phase I

GDC-0941 Genentech Inc Phase II

XL-147 Exelixis Phase I/II

BKM-120 Novartis Phase I

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Drug Drug class Stage of development

PI-103 Dual kinase inhibitor Preclinical

LY294002 Dual kinase inhibitor Preclinical

NVP-BEZ235 Dual kinase inhibitor Phase I/II clinical trials

SF1126 Dual kinase inhibitor Phase I/II

XL765 Dual kinase inhibitor Phase I

BGT226 Dual kinase inhibitor Phase I/II

Dual kinase (mTOR &PI3K) inhibitors:

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DNA damage, double strand breaks are highly toxic to cells

Homologous recombination is DNA repair mechanism.

Homologous recombination is dependent on functional BRCA 1 and 2 pathways.

Germline mutations in either the BRCA1 or BRCA2 genes are associated with a high risk of developing a number of breast cancers.

When the BRCA-associated DNA repair pathway (homologous recombination) – is lost or dysfunctional, repair shifts toward alternate DNA repair mechanisms dependent on a unique class of enzymes, Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP).

Poly-{Adenosine diphosphate (ADP)-Ribose} Polymerase (PARP)

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PARP-inhibitors in clinical development:

Agent Company Stages

Olaparib (AZD2281) AstraZeneca/KuDOS Phase I/II

Veliparib Abbott Phase I/II

BS1-201 BiPar/SanofiAventis Phase II/III

AG014699 Pfizer Phase I/II

MK482 Merck Phase I

INO-1001 Inotek Phase I

CEP9272 Cephalon Phase I

Targeted cancer therapies hold the promise of being more selective, reducing side effects, and improving quality of life.

Targeted therapies may work best in combination, either with other targeted therapies or with more traditional therapies. Researchers are working to find new ways to target cancer cells as part of treatment.

Various targeted therapies are being studied in clinical trials to see how well they work in treating breast cancer.

As more targets are identified and therapies are developed, doctors will be able to offer patients treatment that works best for their type of breast cancer.

In future, metastatic breast cancer, triple negative breast cancer can be well treated.

Conclusion

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References:

1) Harsh Mohan, Chapter 25 The Breast, Textbook of Pathology, Jaypee Brothers Medical Publishers Pvt. Ltd., 6 th ed, Pg. No.754-767, 2010.

2) Bruce A. Chabner, Jeffrey Barnes, Joel Neal, Erin Olson, Hamza Mujajic, Lecia Sequist, Wynham Wilson, Dan. L. Lango, Constantine Mitsiades and Paul Richardson, Chapter 62 Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies and Cytokines, Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Mc Graw-Hill, 12th ed, Pg. No.1731-1750, 2010.

3) Laura Boehnke Michaud and Chad M. Barnett, Chapter 136 Breast Cancer, Pharmacotherapy A Pathophysiologic Approach, Mc Graw Hill, 8th ed, Pg. No. 2229-2266, 2011.

4) Dariusz Pytel, Tomasz Sliwinski, Tomasz Poplawski, Deborah Ferriola and Ireneusz Majsterek, Tyrosine Kinase Blockers: New Hope for Successful Cancer Therapy, Anti-Cancer Agents in Medicinal Chemistry, 9 th ed, Pg. No. 66-76, 2009. 5) Michelle Arkin and Mark M. Moasser, HER2 directed small molecule antagonists, Current Opinion Investigational Drugs, 9(12) Pg. No. 1264–1276, December 2008.

6) Rita Nahta, Gabriel N. Hortobagyi and Francisco J. Esteva, Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention, The Oncologist, 8: Pg. No. 5-17, 2003.

7) Madeleine Hewish, Ian Chau and David Cunningham, Insulin-Like Growth Factor 1 Receptor Targeted Therapeutics: Novel Compounds and Novel Treatment Strategies for Cancer Medicine, Recent Patents on Anti-Cancer Drug Discovery, 4, Pg. No. 54-72,2009.

8) Vikram K. Jain and Nicholas C. Turner, Challenges and Opportunities in The Targeting of Fibroblast Growth Factor Receptors in Breast Cancer, Breast Cancer Research, 2012, 14(3):208,http:// breast-cancer-research.com/content/14/3/208.

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References:

9) Hetty Carraway and Manuel Hidalgo, New targets for therapy in breast cancer: Mammalian target of rapamycin (mTOR) antagonists, Breast Cancer Research, 6(5), Pg. No.219-224, 2004.

10) Denise A. Yardley, Combining mTOR Inhibitors with Chemotherapy and Other Targeted Therapies in Advanced Breast Cancer: Rationale, Clinical Experience, and Future Directions, Breast Cancer: Basic and Clinical Research, Pg. No. 7-22, 2013.

11) Palma Fedele, Nicola Calvani, Antonella Marino, Laura Orlando, Paola Schiavone, Annamaria Quaranta, Saverio Cinieri, Targeted Agents to Reverse Resistance to Endocrine Therapy in Metastatic Breast Cancer: Where Are We Now and Where Are We Going?, Critical Reviews in Oncology/Hematology, 84, Pg. No.243-251, 2012.

12) Carey K. Anders, Eric P. Winer, James M. Ford, Rebecca Dent, Daniel P. Silver, George W. Sledge, and Lisa A. Carey, PARP Inhibition: “Targeted” Therapy for Triple Negative Breast Cancer, Clinical Cancer Research, 16(19), Pg. No.4702-4710, October 1, 2010 . 13) Carey K. Anders, Eric P. Winer, James M. Ford, Rebecca Dent, Daniel P. Silver, George W. Sledge, and Lisa A. Carey, PARP Inhibition: “Targeted” Therapy for Triple Negative Breast Cancer, Clinical Cancer Research, 16(19), Pg. No.4702-4710, October 1, 2010.

14) M. Tenhagen, P. J. Van Diest, I. A. Ivanova, E. Van Der Wall and P. Van Der Groep, Fibroblast Growth Factor Receptors in Breast Cancer: Expression, Downstream Effects, And Possible Drug Targets, Endocrine-Related Cancer, 19, Pg. No.R115–R129, 2012.

15) Nadeem Sheikh, Saba Shehzadi and Arfa Batool, Treatment of Breast Cancer: New Approaches, Cancer Management, Pg. No.85-94 June, 2012.

16) D. Sachdev and D. Yee, The IGF system and Breast Cancer, Endocrine-Related Cancer, 8, Pg. No.197–209, 2001.

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References:

17) Ahmedin Jemal, Freddie Bray, Melissa M. Center, Jacques Ferlay, Elizabeth Ward, and David Forman, Global Cancer Statistics, A Cancer Journal for Clinicians, 61(2), Pg. No. 69–90,2011.

18) Stephen Hiscox, L. Morgan, Tim Green and Robert I. Nicholson, Src as a Therapeutic Target in Antihormone Anti-growth Factor-resistant Breast Cancer, Endocrine-Related Cancer,13, Pg. No. S53–S59, 2006.

19) Dimitrios Zardavas, Jose Baselga and Martine Piccart, Emerging Targeted Agents in Metastatic Breast Cancer, Clinical Oncology, Pg. No.1-20, 2013.

20) Edith A. Perez and Jean-Philippe Spano, Current and Emerging Targeted Therapies for Metastatic Breast Cancer, Cancer, Pg. No.3014-3025, June 15, 2012.

21) Marius Raica and Anca Maria Cimpean, Platelet-Derived Growth Factor (PDGF)/PDGF Receptors (PDGFR) Axis as Target for Antitumor and Antiangiogenic Therapy Pharmaceuticals, 3, Pg. No.572-599, 2010.

22) Line L. Haugan Moi, Marianne Hauglid Flageng, Ingvild S. Fenne1, Jennifer Gjerde, Ernst A. Lien and Gunnar Mellgren, Steroid Receptor Coactivators and Their Expression, Regulation and Functional Role in Endocrine Responsive and Resistant Breast Cancer, Breast Cancer – Carcinogenesis, Cell Growth and Signaling Pathways. Pg. No.715-732, November 2011.

23) Leonel F. Hernandez-Aya, Ana M. Gonzalez-Angulo, Targeting the Phosphatidylinositol 3-Kinase Signaling Pathway in Breast Cancer, The Oncologist, 16, Pg. No.404–414, 2011.

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Thank You