More than 60 years ago, British physician Denis Parsons Burkitt and his associates achieved one of the signal successes in cancer medicine when they cured children in sub-Saharan Africa with a form of lymphoma by treating them with high doses of the chemotherapy drug cyclophosphamide.
Now, Dana-Farber Cancer Institute researchers have shown that the traditional understanding of the drug’s mode of action is incomplete.
In a paper in today’s issue of the journal Cancer Discovery, the researchers demonstrate that large doses of cyclophosphamide not only kill cancer cells directly, as has been known, but also spur an immune system attack on the cells.
The discovery resolves long-standing questions about how cyclophosphamide and other alkylating agents – among the oldest and most widely used types of chemotherapy – work, and suggests a novel way of sparking an immune system strike on certain cancers.
“Our results show that, at high doses, cyclophosphamide and other alkylating agents blur the line between chemotherapy and immunotherapy,” said Dana-Farber’s David Weinstock, MD, the senior author of the study.
“These findings offer insights into how to switch on key immune system cells to augment existing therapies.”
Cyclophosphamide was just the eighth anti-cancer drug to enter standard therapy when it was approved by the U.S. Food and Drug Administration in 1954.
It became a mainstay of cancer treatment after Burkitt and others used high doses to cure children with what’s now known as Burkitt lymphoma – which had a 100% mortality rate at the time – sometimes with only one dose.
Cyclophosphamide and other alkylating agents are now used at lower doses to treat many types of cancer, including breast, ovarian, and pediatric cancers.
Alkylating agents work by attaching chemical components called alkyl groups to cancer cells’ DNA, leading to breaks in the DNA molecule.
The damage undermines the cells’ ability to duplicate their DNA and, ultimately, to divide.
Dana-Farber’s David Weinstock, M.D., explains how Cyclophosphamide acts as both chemotherapy and immunotherapy at high doses. Credit: Dana-Farber Cancer Institute
Over the years, clues emerged that there’s more to the drugs’ effectiveness than damaging DNA. Researchers discovered, for example, that while high doses are much more effective against certain cancers than low doses, they inflict about the same amount of DNA damage, suggesting that something else comes into play at high doses. Sporadic data pointed to the immune system.
Another clue came from pathology studies of Burkitt lymphoma tissue.
“Burkitt lymphoma and other high-grade lymphomas with rearrangements in the MYC gene have a ‘starry sky’ appearance under the microscope, with large numbers of macrophages [a type of immune system cell] dispersed among the lymphoma cells,” Weinstock remarked.
In the new study, investigators focused on the effect of high doses of cyclophosphamide on macrophages – cells that, under the right conditions, eat infected cells or cells in the process of dying.
In mouse models implanted with human lymphoma tissue, the researchers showed that high doses of the drug, but not normal doses, damaged tumor cells in a way that severely stressed the lymphoma cells.
The stressed cells responded by secreting cytokines, substances that summon macrophages to eat the tumor cells.
The researchers analyzed thousands of these macrophages to determine which genes were active, or expressed, in each of them.
They found that one subset, which expresses the proteins CD36 and FcgRIV, has a particularly voracious appetite for stressed lymphoma cells.
Dubbed “super-macrophages,” they devour lymphoma cells, Weinstock said.
Although high doses of cyclophosphamide and other alkylating agents may be too toxic for patients with diseases other than Burkitt lymphoma, researchers are investigating agents that mimic their ability to stress cancer cells, but with milder side effects.
The findings may be especially relevant for the treatment of “double-hit” lymphomas, which are marked by their aggressiveness and for a rearrangement in the MYC gene, Weinstock observed.
Targeted therapies are currently lacking for this disease, which accounts for six to 10% of diffuse large B cell lymphomas and generally has poor outcomes for patients.
Other than surgery, radiotherapy, endocrine therapy, and immunotherapy, chemotherapy is the main treatment for cancer. Patients with different cancers derive more survival benefits through chemotherapy not only at the early stage of disease, but also at the late stage.
However, quite a few cancers develop drug resistance easily and cause relapse and metastasis.
What are the reasons for conventional chemotherapy failure?
First, conventional chemotherapy drugs such as paclitaxel mainly target proliferating cancer cells.
Such drugs kill the majority of proliferating cancer cells, but cannot do so with dormant cancer cells, which can divide into proliferating cancer cells and cause relapses following chemotherapy [1,2].
Thus, targeting only proliferating cancer cells is less efficient.
Conventional drugs such as cyclophosphamide kill both proliferating and dormant cancer cells [3,4].
However, multidrug-resistant mechanisms ensure that a number of cancer cells can resist and escape chemotherapy.
These dormant or resistant cancer cells are the reason for conventional chemotherapy failure, and are considered cancer stem cells [5–7].
Recently, accumulating studies demonstrated that cancer stem cells, a cancer cell subpopulation with unlimited capacity for self-renewal, differentiation, and tumorigenesis, are the reason for relapse and metastasis [8,9].
Initially, conventional chemotherapy and radiotherapy kill most cancer cells and shrink tumors immediately, but the spared cancer stem cells eventually result in relapse and metastasis.
A new therapy targeting a few cancer stem cells may not shrink the tumor in an obvious manner initially, but may eventually disappear due to the loss of self-renewal and proliferation [10] (Figure 1).
Other than inhibiting cancer cells, normal tissues are harmed by conventional chemotherapy, which also causes many side effects, such as bone marrow suppression [11], nausea and vomiting [12], neurotoxicity [13,14], and temporary alopecia [15,16] due to the targeted drug delivery systems being less precise and the targeting drugs being less efficient.
Therefore, enhancing conventional chemotherapy efficacy and reducing its side effects necessitates the search for potential efficient drugs targeting cancer stem cells and designing a novel drug delivery system to transfer such drugs only to cancer sites, and not normal tissues.
Herein, we summarize the methods for enriching cancer stem cells, the search for new efficient drugs, and the delivery of targeted therapy drugs. We also discuss cancer stem cell hierarchy complexity and the corresponding target therapy strategies
Effects of conventional chemotherapy and targeted therapy. Conventional chemotherapy initially kills most cancer cells and shrinks tumor size immediately, but the spared cancer stem cells eventually result in relapse and metastasis. Targeted therapy of cancer stem cells may not shrink the tumor size in an obvious manner at first, but the tumor may eventually disappear due to the loss of self-renewal and proliferation capacity.
More information: Chen Lossos et al, Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents, Cancer Discovery(2019). DOI: 10.1158/2159-8290.CD-18-1393
Journal information: Cancer Discovery
Provided by Dana-Farber Cancer Institute
