Molecular Targeting in the Treatment of Cancer: An Interview With Brian Druker, MD

Sally Church, PhD


March 21, 2005

Editorial Collaboration

Medscape &

Editor's note: Recent results with different tyrosine kinase inhibitors have shown variable results depending on the drug and cancer type, suggesting that there are lessons to be learned from the trials with imatinib and gefitinib. There is growing evidence that tyrosine kinase inhibitors may work consistently and reliably against cancers in which the drug target is constitutively activated by gene mutation as opposed to simply overexpressed. In an interview with Medscape, Dr. Brian Druker, of the Howard Hughes Medical Institute at Oregon Health & Science University in Portland, discussed how researchers are applying the current findings to future cancer research and development.

Medscape: We have seen good progress with the tyrosine kinase inhibitor imatinib mesylate, but it has been the only one that has been very successful so far. Do you think new targets will hold promise for future agents in oncology?

Dr. Druker: Let's first look at imatinib in chronic myeloid leukemia (CML). Is it a one-off kind of result? The skeptics/pessimists might say that imatinib in chronic phase is a pretty low-grade malignancy, with an excess cell proliferation rate and a single target. Or, perhaps we can say that we can diagnose the disease earlier so we can treat earlier.

Either way, the reality is that we are still going to have patients who are coming in with acute leukemias who are relatively advanced and have many mutations. But I still think that there's good reason that understanding molecular targets and targeting therapies has a role and still will be extremely successful. I'll give you a couple of examples. In CML patients in blast crisis, we saw 50% response rates and 20% durability with imatinib; that tells you that a single agent in advanced disease can have significant activity. The same holds true for tamoxifen in metastatic breast cancer, where a single agent targeting a critical pathway has remarkable activity. The same is true for all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL), which also showed remarkable activity. But in all of these advanced diseases, it is clear that single agents need help.

Let me take you through an example of some lab data that is translating into what we see in the clinic. If you look at imatinib's effects on a cell line that is grown in KIT, and you shut down that pathway but provide the cells with other growth factors, you can inhibit their growth by 50%. If you inhibit the growth of a tumor by 50%, you have disease progression because the tumor is still growing, but it isn't growing as quickly. You would not measure that as an end point in most clinical trials, because you would not see tumor shrinkage. If you now target a second growth pathway independent of KIT, the cells are dead. This tells us that we might need to target more than one pathway in an advanced cancer, we just need to understand which pathways to target. This is where the field is going -- to diagnose cancers earlier, when they are simpler to target, or to identify the right combination of targets in an advanced cancer by using multiple agents.

Let's talk about why gefitinib is so disappointing, showing only a 20% response rate. If you look at the trials, there has not been a careful evaluation of whether the epidermal growth factor receptor has been inhibited at the doses of gefitinib that were used. It may be that you have not shut down the receptor all that well. If you don't have those data, you cannot really say whether the trials have been a success or failure. If you did shut down the receptor, you might need to combine the agent with something else. Now we know from the phase 3 trials that the combinations did not work. But that might also be related to the fact that so few patients would have responded to single-agent gefitinib anyway. So one possibility is that the target is not as good as we think, while the other possibility is that there is a subset of patients who respond beautifully, and we just need to identify them.

This kind of paradigm has been proven by Drs. Heinrich and Fletcher,[1] who have looked at gastrointestinal stromal tumors and KIT mutational status. If you have exon 11 mutations, which occur in about 80% of patients, you'll get an 80% to 90% response rate and very good durability. By contrast, if the patient expresses wild-type KIT, has no mutations in KIT but expresses a target for imatinib, the response rate is only about 20%. This tells you that if you examine responding patients carefully, you may understand why your drug is working. It may be that gefitinib could work in only 20% of patients, but if you could identify those patients, you'll have a subgroup of patients with a 70% or 100% response rate.

The trick with molecular targeting is that you have to be able to match the drug to the patient. And until you understand how the drugs work, why they work, and for whom they work, your results might not be as remarkable as you would like for them to be. Once we understand how to match the drug to the patient, I think we will see many, many examples like imatinib.

Medscape: Do you think understanding the biology of mutations will help develop new strategies in overcoming clinical drug resistance?

Dr. Druker: There is no question that if you understand why patients respond and why patients relapse, that is going to help you prevent the relapses or overcome them. The imatinib paradigm is also teaching us another lesson. If you look at newly diagnosed CML patients, resistance is not the major problem, as 97% get to a complete hematologic response. At 30 months, 80% have had a complete cytogenetic response; at 24 months, 55% have had a 3-log or greater reduction in bcr-abl levels by quantitative PCR, but only 5% are molecularly negative. There is a difference between good response and molecular persistence. It may be that over time, the numbers of molecularly negative patients will increase, but I think we need to invest some effort in understanding why we can't completely eradicate the disease. Maybe there are new point mutations that need a combination approach. The more you understand about how to target a cancer, the better your treatment strategies are going to be.

Medscape: Which presentations have particularly interested you at this meeting?

Dr. Druker: Three presentations have interested me at the meeting. The first is on FLT3, which would be one of my choices for a very good molecular target. One of the exciting presentations is on one of the FLT3 inhibitors, PKC 412, which is showing very good responses.[2] Durability has not been that great, but FLT3 inhibitors in patients with FLT3 mutations have biologic activity. It may need to be combined with other agents, much like ATRA in APL or imatinib in blast crisis of CML, but it clearly has activity. It validates the paradigm of molecularly targeted therapy.

A second was on arsenic trioxide and ATRA in APL.[3] Both ATRA and arsenic trioxide target the PML-RAR-alpha fusion protein in APL, but one targets the retinoic acid binding region, the other targets it for degradation. Currently, the US clinical trials use these two agents sequentially -- ATRA up front then arsenic in maintenance.[4] The Chinese group used arsenic trioxide plus ATRA up front together and got a very high remission rate and very good durability.[3] That tells you that you can combine targeted agents and see even better results.

The third presentation that I think is intriguing, even though data are very early, is the study by Dr. List's group of CC-5013 in 5q- myelodysplasia, where they were seeing cytogenetic responses and remissions.[5] That is a disease that has a very poor prognosis, and you would not expect a high level of response to chemotherapy. However, here is an agent, a thalidomide derivative, whose mechanism of action is unclear, but even in preliminary stages, the fact that you can see some remarkable responses is very encouraging indeed.

Disclosures: Dr. Druker has no significant financial interests to disclose.

  1. Fletcher JA, Corless CL, Dimitrijevic S, et al. Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST). Proc Am Soc Clin Oncol. 2003;22:815. Abstract 3275.

  2. Bali P, George P, Tao J, et al. Combination of histone deacetylase inhibitor LAQ824 and the FLT 3 kinase inhibitor PKC412 is highly active against human AML cells with constitutively active mutant FLT 3 tyrosine kinase Blood 2003 102 97a. Combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 is highly active against human AML cells with constitutively active mutant FLT-3 tyrosine kinase. Blood. 2003;102:97a. Abstract 328.

  3. Shi A, Shen Z, Fang J, et al. Induction maintenance with ATRA As2O3 combination yields a high quality clinical molecular remission and disease free survival in newly diagnosed patients with acute promyelocytic leukemia Blood 2003 102 141a. Induction/maintenance with ATRA/As2O3 combination yields a high quality clinical/molecular remission and disease-free survival in newly diagnosed patients with acute promyelocytic leukemia. Blood. 2003;102:141a. Abstract 486.

  4. Wang ZY. Ham-Wasserman Lecture: Treatment of acute leukemia by inducing differentiation and apoptosis. Hematology (Am Soc Hematol Educ Program). 2003;:1-13.

  5. List AF, Kurtin S, Glinsmann-Gibson B, et al. Efficacy and safety of CC5013 for treatment of anemia in patients with myelodysplastic syndromes MDS Blood 2003 102 184a. Efficacy and safety of CC5013 for treatment of anemia in patients with myelodysplastic syndromes (MDS). Blood. 2003;102:184a. Abstract 641.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: