Update in Hematology Oncology Targeted Therapies Mark Holguin
25 years ago Why I chose oncology People How to help people with possibly the most difficult thing they may have to deal with Science Turning the emerging knowledge of the molecular basis of malignancy into effecfve and non- toxic therapy
TradiFonal chemotherapy Standard treatment for cancer during the last several decades has been intravenous chemotherapy Targets rapidly dividing cells, malignant and normal Many successes Pediatric acute leukemia TesFcular cancer Decreasing number of new chemotherapy agents being tested and approved
Chemotherapy Side Effects
Targeted therapy Drugs or anfbodies that block the growth and spread of cancer by interfering with specific molecules (targets) involved in cancer growth. Promises treatment specific to malignant cells and avoids toxicity to normal Fssues. Generally categorized as either monoclonal anfbodies or small molecules Monoclonal anfbodies designed to interact with cell surface anfgens Frequently humanized Small molecules are capable of diffusing into cells and act on intracellular targets IdenFfied in large scale screens for interacfng with target
Breast Cancer Breast cancer treatment uses surgery, radiafon and chemotherapy to treat and possibly cure early stage breast cancers MetastaFc breast cancer will frequently respond to tradifonal chemotherapy Not curafve treatment Average durafon of response ~6 months
First Targeted Therapy First molecular target was the estrogen receptor of breast cancer cells. Tamoxifen Binds to the estrogen receptor and blocks signal transducfon Developed as birth control agent in 1960 s. InvesFgators quickly appreciated its potenfal for treatment of breast cancer
Tamoxifen
Tamoxifen Oral agent with minimal side effects Hot flashes, risk of blood clot, endometrial cancer In 1970 s showed good response rates in metastafc breast cancer that express estrogen receptors. DuraFon of response beber than with chemotherapy In 1990 s adjuvant therapy given for 5 years reduced recurrence rates of breast cancer ader surgery by ~50%
HER2 Breast cancer prognosfc factors ER status, tumor size, stage, grade Expression of Her 2 Her2 (human epidermal growth factor receptor 2) a surface protein that interacts with an unknown ligand acfvates proliferafve signaling pathways Her2 is over expressed on ~30% of breast cancer and confers poor prognosis Overexpression mediated by gene amplificafon TesFng for HER2 expression now standard in breast cancer
HercepFn HercepFn (Trastuzumab) Humanized monoclonal anfbody binding to Her2 ToxiciFes primarily infusion reacfons Cardiac toxicity Given as 1-2 hour infusion either weekly or every 3 weeks Treatment of metastafc disease Select cases dramafc responses Usually given along with chemotherapy Adjuvant treatment Reduces recurrence rate by 50% 1 year course
Non Hodgkins Lymphoma Divided into aggressive and indolent Aggressive Grow quickly, lethal, potenfally curable ~50% cure rate with CHOP chemotherapy Toxic with hair loss, nausea, myelosuppression Indolent Grow slowly, prolonged survival, not curable Responds well to a variety of chemo CHOP, CVP, BendamusFne
Rituximab A monoclonal anfbody targefng CD20 protein that is expressed on surface of B lymphocytes Humanized to prevent immune reacfon ToxiciFes primarily infusion reacfon Decreased normal B cell funcfon well tolerated Unlike HercepFn, no cardiac toxicity
Rituximab Treatment of indolent B cell lymphoma Enhances chemotherapy response rates Used alone over half of pafents will respond 4 weekly treatments Can be repeated at relapse Not curafve
Rituximab Treatment of aggressive lymphoma Response rates low (15%) used alone Enhances response and survival rates when combined with chemotherapy With limited toxicifes and broad applicability, Rituximab used in essenfally all mature B cell malignancies Vitamin R
Chronic myelogenous leukemia MyeloproliferaFve disorder Myeloid proliferafon Philadelphia chromosome (9:22 translocafon) TranslocaFon results in fusion gene BCR- ABL with enhanced proliferafon signaling Fatal disease Conversion to resistant AML in ~5 years Treatment Only curafve treatment is allo BMT Hydroxyurea controls blood counts but doesn t alter natural history
ImaFnib (Gleevec) Small molecule that binds to the BCR- ABL gene product InacFvates signaling Leads to apoptosis Oral agent taken daily ToxiciFes Myelosuppression Edema Headache
ImaFnib (Gleevec) Treatment with Gleevec Over 90% blood count and symptom control (hematologic remission) Over 70% will become negafve for Ph chromosome in cytogenefc tesfng (karyotypic remission) ~50% will have three log decrease in BCR- ABL transcript by peripheral blood PCR (major molecular remission PaFents with karyotypic remission have improved survival compared to allo BMT Probably not curafve
ImaFnib (Gleevec) Name was a problem for FDA approval Glivec changed to Gleevec Two addifonal agents DasaFnib (Sprycel) NiloFnib (Tasigna) CML in the Gleevec era
Melanoma Early stage disease curable with surgery PaFents with nodal metastases at high risk of recurrence ader surgery Adjuvant treatment with interferon controversial Distant metastafc disease generally incurable High dose IL- 2 ~5% cure Standard chemotherapy offers ~15% chance of response, high toxicity, no cures
BRAF BRAF is a member of a serine- threonine kinase family Regulates/modulates the MAP kinase signaling pathway affecfng cell division and differenfafon Inherited mutafons in BRAF cause birth defects Acquired mutafons in BRAF can cause cancer (Proto- oncogene) Approximately 60% of melanomas contain a common V600E mutafon in the BRAF gene
Vemurafinib (PLX4032, Zelboraf) Oral small molecule that targets the mutated BRAF protein Toxicity Skin rash, fafgue, arthralgia, skin cancer IniFal phase I and II studies in metastafc melanoma pafents show responses ~80 parfal response rate ~5% complete response Median durafon of response over 7 months
Vemurafinib (PLX4032, Zelboraf) Experience is limited as yet, but excifng response rate in a disease known for resistance to therapy Bar set low in melanoma Proof of value of drug discovery/development systems
Cost Major problem with targeted therapies is cost Gleevec $5000 to $8000 monthly HercepFn adjuvant treatment ~$75,000 Assistance programs Social work help PaFents with no insurance many Fmes beber able to get drug than those with some insurance
Summary Targeted therapies have made large strides in the last decade Improved treatment for many cancers Proof of drug discovery/development systems established Likely to see new drugs being developed at an increasing rate Cost remains a problem