Since 2004, ten antiangiogenic (AA) drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors' WQblood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiotherapy, chemotherapy, and immunotherapy. In my presentation, I will summarize the following lessons learned from pre-clinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases:

1) Solid tumors develop resistance to targeted therapies including AA therapies

2) Why alleviating hypoxia is critical for improving cancer treatment

3) AA agents can normalize the tumor vasculature and alleviate hypoxia

4) Increased tumor perfusion/oxygenation appears to confer survival benefit

5) Benefits of vascular normalization are AA-dose and drug-size dependent

6) Potential of overcoming resistance to AA therapy using biomarkers

7) Targeting VEGF versus VEGFR2 may have a different outcome

8) Blood vessels are not the only target of antiangiogenic agents

9) Agents targeting oncogenic pathways can also normalize tumor vessels

10) Combining antiangiogenic agents with drugs that target oncogenic pathways

11) Combining antiangiogenic agents with vessel decompressing agents

12) Vascular normalization can improve immunotherapy

13) Lower normalizing doses of AA could lower toxicities

14) The normalization strategy can benefit patients with nonmalignant diseases

AA therapy, despite being given to unselected patients, has benefited numerous patients worldwide who had no other alternative treatment options. Similar to various therapeutic approaches that looked straightforward in the beginning, antiangiogenesis has turned out to be more complex and nuanced than originally envisaged for the following reasons:

First, a major part of the complexity in AA therapy stems from multiple mechanisms employed by tumors to recruit blood vessels. These mechanisms seem to vary not only spatially and temporally within a tumor, but also between a primary tumor and its metastases, and among tumor types. Moreover tumors may switch from one mechanism to another during growth and in response to treatment. While VEGF seems to be a central player in sprouting angiogenesis, our knowledge of the molecular players in other mechanisms is still in its infancy. Understanding these mechanisms in more detail will allow development of novel agents to target all types of tumor vessels and enhance the treatment outcomes from these agents via vascular normalization and/or starvation.

Second, the initial focus of antiangiogenic therapy was to target endothelial cells, pericytes and/or the basement membrane they are invested in. Now we know that these cells interact not only with each other and cancer cells, but also with the extracellular matrix and other stromal cells in the tumor microenvironment, including the resident and transiting immune cells, cancer stem cells as well as fibroblasts/myofibroblasts.

Third, not only blood vessels, but also other components of the tumor microenvironment are abnormal and all these abnormalities in concert seem to fuel tumor progression and treatment resistance. Thus, we need to develop therapeutic agents that normalize the entire tumor microenvironment, including immune and other stromal cells, and not just the tumor blood vessels.

Finally, unlike cancer cell targeted therapies, many AA agents are not directly cytotoxic, but directly affect the vascular permeability. This makes interpreting contrast-enhanced images complicated. Hence, the search for biomarkers has been challenging. Most biomarker studies have focused on circulating biomarkers that are unable separate the response of host from that of neoplastic lesions. Future trials with novel agents need to integrate all three types of biomarkers.

Addressing these challenges and judiciously using existing and newly developed AA agents, alone or with other emerging therapeutic approaches, is likely to increase survival benefits in selected patients, while sparing other patients from unnecessary and expensive treatments.

Reference: This extended abstract is excerpted from the following Perspective:

Jain RK. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell 26: 605-622 (2014)

Citation Format: Rakesh K. Jain. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA03.