Chapter 080. Cancer Cell Biology and Angiogenesis (Part 18) doc

Cancer Cell Biology and Angiogenesis Part 18 Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer

Chapter 080 Cancer Cell Biology

and Angiogenesis

(Part 18)

Antiangiogenic Therapy

Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer treatment Acquired drug resistance

of tumor cells due to their high intrinsic mutation rate is a major cause of treatment failure in human cancers ECs comprising the tumor vasculature are genetically stable and do not share genetic changes with tumor cells; the EC apoptosis pathways are therefore intact Each EC of a tumor vessel helps provide nourishment to many tumor cells, and although tumor angiogenesis can be driven

by a number of exogenous proangiogenic stimuli, experimental data indicate that

at least in some tumor types, blockade of a single growth factor (e.g., VEGF) may inhibit tumor-induced vascular growth Angiogenesis inhibitors function by

targeting the critical molecular pathways involved in EC proliferation, migration, and/or survival, many of which are unique to the activated endothelium in tumors Inhibition of growth factor and adhesion-dependent signaling pathways can induce

EC apoptosis with concomitant inhibition of tumor growth Different types of tumors use distinct molecular mechanisms to activate the angiogenic switch Therefore, it is doubtful that a single antiangiogenic strategy will suffice for all human cancers; rather, a number of agents will be needed, each responding to distinct programs of angiogenesis used by different human cancers

Four randomized phase III clinical trials have demonstrated that the addition of bevacizumab (Avastin; a humanized monoclonal antibody that binds and inhibits VEGF) to chemotherapy results in significantly improved response rates, progression-free survival, and overall survival when compared to treatment with chemotherapy alone (Table 80-3) This effect was shown in the first-line treatment of patients with advanced colon, lung, and breast cancers, and in the second-line treatment of colon cancer However, not all trials have been positive;

in previously treated breast cancer, the addition of bevacizumab to capecitabine (an oral fluoropyrimidine) did not increase efficacy, and in previously untreated pancreatic cancer, bevacizumab did not enhance the efficacy of gemcitabine

Table 80-3 Randomized Phase III Clinical Trials Demonstrating the Efficacy of Bevacizumab in Combination with Chemotherapy for the

Treatment of Advanced Cancers

Tu

mor Type

Stage

of Disease

Previ ous

Treatment

Num ber of Patients

Chemothe rapy Regimen

Outc ome

Col

on cancer

Metas tatic

+ 5-FU/LV ± bevacizumab

Incre

(20.3 vs 15.6 months), PFS (10.6 vs 6.2 months),

(44.8 vs 34.8%)

Col

on cancer

Metas tatic

Seco

nd line;

previous irinotecan/5 -FU

± bevacizumab

Incre

(12.9 vs 10.8 months), PFS (7.2 vs

4.8 months),

RR (21.8 vs 9.2%)

Non

-small cell

lung

cancer

(excluding

squamous

histology)

Metas tatic

num + paclitaxel

± bevacizumab

Incre

(12.5 vs 10.2 months), PFS (6.4 vs 4.5 months),

RR (27.2 vs 10.0%)

Bre

ast cancer

Recur

metastatic

± bevacizumab

Incre ased PFS (11.0 vs 6.2 months), RR (28 vs 14%)

Note: 5-FU, 5-fluorouracil; LV, leucovoran; OS, overall survival; PFS,

progression-free survival; RR, response rate; FOLFOX, folinic acid (LV), 5-FU,

and oxaliplatinum