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9 Radiation therapy Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Chemotherapy Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Hormone therapy Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing. Hormones are substances made by glands in the body and circulated in the bloodstream. Targeted therapy Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.

10 Monoclonal antibodies and tyrosine kinase inhibitors are two types of targeted therapies used in the treatment of breast cancer. Trastuzumab is a monoclonal antibody that blocks the effects of the growth factor protein HER2, which sends growth signals to breast cancer cells. About one-fourth of patients with breast cancer have tumors that may be treated with trastuzumab combined with chemotherapy. Pertuzumab is a monoclonal antibody that may be combined with trastuzumab and chemotherapy to treat breast cancer. It may be used to treat certain patients with HER2-positive breast cancer that has metastasized (spread to other parts of the body). It may also be used as neoadjuvant therapy in certain patients with early-stage HER2-positive breast cancer. Ado-trastuzumab emtansine is a monoclonal antibody linked to an anticancer drug. This is called an antibody-drug conjugate. It is used to treat HER2-positive breast cancer that has spread to other parts of the body or recurred (come back). Tyrosine kinase inhibitors are targeted therapy drugs that block signals needed for tumors to grow. Tyrosine kinase inhibitors may be used with other anticancer drugs as adjuvant therapy. Lapatinib is a tyrosine kinase inhibitor that blocks the effects of the HER2 protein and other proteins inside tumor cells. It may be used with other drugs to treat patients with HER2-positive breast cancer that has progressed after treatment with trastuzumab. PARP inhibitors are a type of targeted therapy that block DNA repair and may cause cancer cells to die. PARP inhibitor therapy is being studied for the treatment of triple-negative breast cancer.

11 INIBITORI DELL'AROMATASI

16 When behavioral (neuro)endocrinology began to crystallize as a separate scientific discipline, one early hypothesis was that males display maletypical behaviors such as mount and intromission because they are exposed to male typical hormones, primarily testosterone (T) secreted by their testes, while females display female-typical behaviors (e.g., lordosis in rodents or squatting in chickens) due to the action on their brain of female-typical hormones, i.e., the ovarian steroids, 17b-estradiol (E2) and progesterone. It was soon apparent, however, that estrogens are able to activate the same behaviors as T in males. These puzzling findings, as well as many others that followed, progressively resulted in the idea that somehow T can be transformed in the brain into E2 before it produces its behavioral effects. Fred Naftolin and his coworkers to investigate the ability of the central nervous system itself to aromatize androgens.

18 Management of hormone receptor-positive breast cancer: the latest evidence and future directions Approximately three quarters of all invasive breast tumors are estrogen receptor (ER)- and/or progesterone receptor (PR)-positive, including at least half of all cancers in premenopausal Women. The natural history of hormone receptor (HR)-positive disease differs from that of HR-negative disease in terms of time to recurrence, site of recurrence, and overall aggressiveness of the disease. Compared with patients with ER-negative tumors, patients with ER-positive tumors experience a relatively constant hazard of recurrence over time. In women treated with tamoxifen for 5 years, more than half of all recurrences occur in years 6 15 after diagnosis. Although tamoxifen and aromatase inhibitors (AI) lower the risk of recurrence for several years after they are stopped, late recurrences and deaths remain a major clinical challenge. In the metastatic setting, there are some patients with HR-positive disease who have durable response to antiestrogen therapy, although the majority of patients will have a short survival of < 3 years.

19 Clinical Efficacy and Mechanism of Action Aromatase inhibition represents one of the main endocrine treatment treatment options in post-menopausal metastatic breast cancer. The first of these to be used in clinical practice was formestane. Aromatase, a member of the cytochrome P450 (CYP) enzyme family, is a product of the CYP19 gene and is the rate-limiting step in the conversion of androstenedione to estrone and of testosterone to estradiol. The CYP19 gene is highly expressed in the human placenta and in the granulosa cells of the ovarian follicles. Non-glandular tissues having lower levels of aromatase activity include subcutaneous, fat, liver, muscle, brain, normal breast, and breast cancer tissues. The activity of the enzyme is increased by alcohol, advanced age, obesity, insulin, and gonadotropins.

20 Aromatase inhibitors are indicated for adjuvant endocrine therapy in postmenopausal but not premenopausal women. Approximately 95% of estrogen production in premenopausal women occurs in the ovary, whereas conversion of adrenal androgens to estrogen is the predominant source of estrogen production in postmenopausal women. Aromatase inhibitors are not used in premenopausal women because the hypothalamic-pituitary-ovarian axis is activated in response to the decrease in systemic levels of estrogen after AI administration. This activation results in an increase in gonadotropin secretion and in ovarian production of estrogen, androgen, and aromatase. Aromatase inhibitors are classified as steroidal (type I) or nonsteroidal (type II) inhibitors. Exemestane, a steroidal inhibitor that is a structural derivative of androstenedione (the substrate of aromatase), irreversibly inhibits the aromatase enzyme. In contrast, the nonsteroidal compounds letrozole and anastrozole reversibly bind to the aromatase enzyme.

21 Around the same time that selective aromatase inhibitors were in development, aminoglutethimide, a drug that was initially used as an anti-epileptic drug, was found to suppress adrenal steroid production by inhibiting multiple cytochrome P450 enzymes. Since adrenalectomy has also been used to treat breast cancer, Richard Santen and colleagues started to use aminoglutethimide as a medical adrenalectomy for breast cancer. In the fall of 1981, Angela Brodie went to give a presentation in Rome about her research. Hearing her presentation, Charles Coombes expressed an interest to conduct a clinical trial with 4-hydroxy-androstenedione (4-OH)-A to treat breast cancer. Soon after, 4- OH-A was renamed to FORMESTANO and became the first selective aromatase inhibitor used clinically for the treatment of breast cancer. This breakthrough has sparked and inspired the later development of a wide variety of AIs.

22 Current AIs can be classified into two subtypes, namely steroidal and nonsteroidal AIs (Table 1). Given that some the AIs have steroid-like structure similar to the aromatase substrate, androstenedione, this subtype of AIs has been termed steroidal AIs or type I inhibitor. Due to its similarity, these AIs bind to the substratebinding site of aromatase enzyme. After binding, they are converted to a reactive intermediate that covalently bind to the enzyme causing irreversible inaction. These inhibitors are also known as suicide inhibitor because the enzyme is inactivated by its own function. This subtype of AIs includes formestane and exemestane. For type II inhibitor or non-steroidal AIs, these AIs bind non-covalently to the heme moiety of the aromatase enzyme and prevent binding of androgens by saturating the binding-site. Unlike steroidal inhibitors, inhibition by this type of AIs is reversible by competitive inhibition of androgens. This particular subtype includes fadrozole, vorozole, rogletimide, letrozole and anastrozole.

25 PHYTOCHEMICAL INHIBITORS

26 Resistance to Aromatase Inhibitors While AIs are a very effective treatment, their benefit is often limited by emergence of resistance which can occur in a significant number of patients in the adjuvant setting and is inevitable in metastatic breast cancer. There appeared to be no cross resistance between steroidal and nonsteroidal AIs regardless of the sequence, switching between these two subtypes can produce 0 26% objective response rates. While the response rates are small, the substantial percentage of patients (50 62%) achieved stable disease of more than 6 months. The large randomized phase III trial comparing exemestane vs. fulvestrant for second line endocrine therapy after progressing on a non-steroidal AI showed a clinical benefit rate of 32.2% vs (p = 0.853) but a rather short median time to progression of 3.7 months in both groups.

27 Aromatase inhibitor-induced arthralgias Musculoskeletal symptoms have arisen as important adverse effects of AIs. In the major phase III clinical trials that compared AI to tamoxifen, the reported incidence of musculoskeletal symptoms ranged from 5 to 36%. However, case series have reported an even higher incidence of emergence of new or worsening joint symptoms in up to 61% of AI-treated women. By contrast, tamoxifen has not been associated with increased joint symptoms. While AI-induced arthralgias were reported as mild to moderate in severity and did not result in significant discontinuation of medication in the large trials.

30 Mammalian target of rapamycin (mtor) inhibitors

31 Rapamycin is an FDA approved drug for the prevention of immunorejection following organ transplantation Rapamicina detta anche Sirolimus Used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin- 2 (IL-2). It was approved by the FDA in September 1999 and is marketed under the trade name Rapamune by Pfizer. Sirolimus was discovered by Brazilian researchers as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island an island also known as Rapa Nui.

32 mtor pathway and cell proliferation Figure 3 Growth factors and mammalian target of rapamycin pathways. PI3K: Phosphoinositide 3-kinase; mtor: Mammalian target of rapamycin; IGF: Insulin like growth factor; EGF: Epidermal growth factor; TGF: Transforming growth factor; VEGF: Vascular endothelial growth factor; ER: Estrogen receptor; TSC: Tuberous sclerosis complex.

33 mtor pathway and angiogenesis mtor activation, beside other activities, stimulates translation of hypoxia inducible factor-1α (HIF-1α), which ultimately increases production of proangiogenic factors such as VEGF-A and other molecules such as those involved in glucose transport. Deregulation of mtor patways and risk of cancer Deregulation of the mtor-linked pathways increases the risk of developing cancer or have been identified in many cancers (Figure 4).

34 Figure 4 Mammalian target of rapamycin pathway is deregulated by mutations in cancer. PI3K: Phosphoinositide 3-kinase; mtor: Mammalian target of rapamycin; IGF: Insulin like growth factor; EGF: Epidermal growth factor; VEGF: Vascular endothelial growth factor; ER: Estrogen receptor; TSC: Tuberous sclerosis complex; PTEN: phosphatase and tensin homologue delated on chromosome.

36 PI3K/mTOR Inhibitors BEZ235 NCT Phase I; BKM120 or BEZ235 and capecitabine in MBC NCT Phase Ib/II; BEZ235 with paclitaxel in HER2, advanced breast cancer or MBC XL765 NCT Phase I/II; XL147 or XL765 with letrozole in HR+, HER2 breast cancer refractory to an AI

37 mtor inhibitors Everolimus NCT Phase II; trastuzumab or everolimus in hormone refractory, ER+ MBC Temsirolimus NCT Phase I/II; temsirolimus with neratinib in HER2+ or triple negative MBC Ridaforolimus NCT Phase II; in combination with trastuzumab in HER2+ trastuzumab-refractory MBC NCT Phase II; in combination with dalotuzumab versus standard of care in HR+ breast cancer NCT Phase II; in combination with exemestane with or without dalotuzumab in HR+ breast cancer AZD-8055 NCT Phase I; solid tumors, completed OSI-027 NCT Phase I; solid tumors or lymphoma, completed INK-128 (MLN0128)

40 PARP inhibitors Olaparib (AZD 2811) Olaparib, formerly known as AZD 2811, has been the PARP inhibitor most extensively studied in breast cancer to date Veliparib Veliparib, also known as ABT-888, has had extensive clinical testing in breast cancer, although almost entirely in combination with cytotoxic chemotherapy, and thus acting as a chemosensitizer rather than seeking to induce synthetic lethality in the setting of BRCA mutation. Rucaparib Rucaparib, also known as AG and PF , has similar PARP catalytic inhibitory activity to olaparib and niraparib, as well as similar PARP-trapping activity.40

6/22/2017 TARGETING THE TARGETS IN 2017 TARGETING THE TARGETS IN 2017

6/22/2017 TARGETING THE TARGETS IN 2017 TARGETING THE TARGETS IN 2017 TARGETING THE TARGETS IN 2017 Primary Care Focus Symposium July 1, 2017 Grace Wang MD I do not have any relevant financial relationships to disclose at this time TARGETING THE TARGETS IN 2017 What are